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Background and Aims: Accelerated atrial pacing offers potential benefits for patients with heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF), compared with standard lower-rate pacing. The study investigates the relationship between atrial pacing rate and left-heart filling pressure., Methods: Seventy-five consecutive patients undergoing catheter ablation for AF underwent assessment of mean left atrial pressure (mLAP) and atrioventricular (AV) conduction delay (PR interval) in sinus rhythm and accelerated atrial pacing with 10 bpm increments up to Wenckebach block. Computer simulations (CircAdapt) of a virtual HFpEF cohort complemented clinical observations and hypothesized the modulating effects of AV coupling and atrial (dys)function., Results: In the study cohort, 49(65%) patients had a high HFpEF likelihood (H2FPEF ≥ 5.0), and 28(37%) an elevated mLAP ≥ 15 mmHg at sinus rhythm. Optimal pacing rates of 100 [70-110]bpm (median [IQR]) significantly reduced mLAP from 12.8 [10.0-17.4]mmHg in sinus rhythm (55 [52-61]bpm) to 10.4 [7.8-14.8]mmHg (P < .001). Conversely, higher pacing rates (130 [110-140]bpm) significantly increased mLAP to 14.7 [11.0-17.8]mmHg (P < .05). PR interval and, hence, AV conduction delay prolonged incrementally with increasing pacing rates. Simulations corroborated these clinical findings, showing mLAP reduction at a moderately increased pacing rate and a subsequent increase at higher rates. Moreover, simulations suggested that mLAP reduction is optimized when AV conduction delay shortens with increasing rate., Conclusions: Accelerated pacing acutely reduces left-heart filling pressure in patients undergoing AF catheter ablation and computer simulations with HFpEF features, suggesting it as a potential therapeutic strategy to alleviate congestion symptoms. Virtual HFpEF patient cohorts hypothesize that AV sequential pacing may further optimize this therapy's beneficial effects., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Current guidelines recommend suspecting transthyretin amyloid cardiomyopathy (ATTR-CM) in patients over 65 years of age with unexplained left ventricular (LV) hypertrophy in a non-dilated LV, heart failure (HF) and preserved ejection fraction (HFpEF), hypertrophic cardiomyopathy or severe aortic stenosis. However, there is evidence indicating a high prevalence of ATTR-CM in other HF phenotypes. As such, this study aimed to characterize the diversity of HF phenotypes of ATTR-CM by examining the LV ejection fraction and LV dilatation using echocardiography., Methods: This multicentre, retrospective observational study included patients diagnosed with ATTR-CM between 2015-2023. The diagnosis was based on a positive cardiac biopsy or positive bone scintigraphy without monoclonal gammopathy. Echocardiographic measurements were categorized according to LV ejection fraction (LVEF) into HFpEF (LVEF ≥50%), HF with mildly reduced EF (HFmrEF, LVEF 40-49%), and HF with reduced EF (HFrEF, LVEF <40%). LV cavity size was categorized by LV end-diastolic diameter (LVEDD) and volume index (LVEDVi) as normal, moderately increased and severe dilatation., Results: The study included 135 patients with ATTR-CM (mean age, 78 years; 89% male; 89% wild-type ATTR-CM). Most patients were screened for ATTR-CM because of unexplained HF and increased LV wall thickness (57%). Echocardiography showed LVEF <50% in 60% of the patients, with a significant portion presenting with HFrEF. Patients with LVEF <50% had higher NYHA class and elevated N-terminal pro-B-type natriuretic peptide levels than HFpEF patients. LV dilatation was observed in 43% of the patients, with 10% presenting with both LVEF <50% and severe LV dilatation., Conclusion: This study revealed significant variability in HF phenotypes among patients with ATTR-CM, from HFpEF without LV dilatation to HFrEF with severe LV dilatation. Relying solely on HFpEF for screening may lead to under-diagnosis. These findings suggest the need for more comprehensive diagnostic criteria beyond echocardiographic measures to improve ATTR-CM detection and management.

Background: We conducted a volume-outcome (V-O) meta-analysis of PEA procedures for chronic thromboembolic pulmonary hypertension (CTEPH), to objectively determine the minimum required annual case load that can define a high-volume centre., Methods: Three electronic databases were systematically queried until May 1st, 2024. Centres were divided in volume tertiles (Ts). The primary outcomes were early mortality and long-term survival. Restricted cubic splines were used to demonstrate the V-O relation, and the elbow-method was applied to define high-volume centres. Long-term survival was assessed using Cox-frailty models., Results: Fifty-one centres (52 consecutive cohorts) were included and divided in tertiles (T1: <6 cases/year, T2: 6-15 cases/year, T3: >15 cases/year), comprising a total of 11 345 patients (mean age 52.3 years). Overall early mortality was 6.0% (T1: 11.6%, T2: 7.2%, T3: 5.2%, p<0.001), for which a significant non-linear volume-outcome relation was observed (p=0.0437) with a statistically determined minimally required volume of 33 cases/year (95% confidence interval [CI] 29-35 cases), and a modelled volume of 40 cases/year corresponding to a 5.0% mortality rate. Nevertheless, early mortality still progressively declined in higher volume centres (from 6.7% to 5.4% to 2.9% in centres performing 16-50, 51-100, and >100 procedures annually). In addition, a significant effect of volume was observed for long-term survival (adjusted hazard ratio per tertile 0.75, 95%CI 0.63-0.89, p=0.001)., Conclusion: There is a significant association between procedural volume and early mortality in PEA. An annual procedural volume of >33-40 cases/year may define a high-volume centre, although higher volumes still lead to progressively lower mortality rates., (Copyright ©The authors 2024.)

Background: The role of cellular senescence in human heart failure (HF) remains unclear. The senescence-associated secretory phenotype (SASP) is composed of proteins released by senescent cells. We assessed the prognostic significance and biologic pathways associated with the SASP in human HF using a plasma proteomics approach., Methods and Results: We measured 25 known SASP proteins among 2248 PHFS (Penn HF Study) participants using the SOMAScan V4 assay. We extracted the common variance in these proteins to generate SASP factor scores and assessed the relationship between these SASP factor scores and (1) all-cause death and (2) the composite of death or HF hospital admission. We also assessed the relationship of each SASP factor to 4746 other proteins, correcting for multiple comparisons, followed by pathway analyses. Two SASP factors were identified. Both factors were associated with older age, lower estimated glomerular filtration rate, and more advanced New York Heart Association class, among other clinical variables. Both SASP factors exhibited a significant positive association with the risk of death independent of the Meta-Analysis of Global-Group in Chronic HF score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. The 2 identified SASP factors were associated with 1201 and 1554 proteins, respectively, belonging to various pathways including the coagulation system, complement system, acute phase response signaling, and retinoid X receptor-related pathways that regulate cell metabolism., Conclusions: Increased SASP components are independently associated with adverse outcomes in HF. Biologic pathways associated with SASP are predominantly related to coagulation, inflammation, and cell metabolism.

Background: Kidney disease is common in heart failure with preserved ejection fraction (HFpEF). However, the biologic correlates and prognostic significance of kidney injury (KI), in HFpEF, beyond the estimated glomerular filtration rate (eGFR), are unclear., Methods and Results: Using baseline plasma samples from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, we measured the following KI biomarkers: cystatin-C, fatty acid-binding protein-3, Beta-2 microglobulin, neutrophil gelatinase-associated lipocalin, and kidney-injury molecule-1. Factor analysis was used to extract the common variability underlying these biomarkers. We assessed the relationship between the KI-factor score and the risk of death or HF-related hospital admission in models adjusted for the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. We also assessed the relationship between the KI factor score and ~5000 plasma proteins, followed by pathway analysis. We validated our findings among HFpEF participants in the Penn Heart Failure Study. KI was associated with the risk of death or HF-related hospital admission independent of the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. Both the risk score and eGFR were no longer associated with death or HF-related hospital admission after adjusting for the KI factor score. KI was predominantly associated with proteins and biologic pathways related to complement activation, inflammation, fibrosis, and cholesterol homeostasis. KI was associated with 140 proteins, which reproduced across cohorts. Findings regarding biologic associations and the prognostic significance of KI were also reproduced in the validation cohort., Conclusions: KI is associated with adverse outcomes in HFpEF independent of baseline eGFR. Patients with HFpEF and KI exhibit a plasma proteomic signature indicative of complement activation, inflammation, fibrosis, and impaired cholesterol homeostasis.

Pulmonary hypertension (PH) is a serious condition linked to immune-system dysfunction. Myositis-specific/associated antibodies (MSAs/MAAs) play a role in idiopathic inflammatory myopathy (IIM) and interstitial lung disease (ILD), but their significance in PH remains unclear. We believe the presence of these antibodies may be underestimated. This study analyzed adult PH patients without pre-existing IIM for MSA/MAA prevalence using a line-blot assay. We compared PH patients with and without ILD signs to a cohort clinically suspected of IIM/ILD ( n = 558). Our PH cohort ( n = 121) showed a significantly higher prevalence of overall weak positive MSAs/MAAs and positive overlap syndrome-associated MAAs than the suspected IIM/ILD group ( p < 0.001). Notably, MSAs/MAAs were found in PH patients both with and without ILD, though more prevalent in those with ILD. Anti-synthetase and anti-overlap syndrome antibodies were the most common. Our study is the first to systematically show a high MSA/MAA prevalence in PH without IIM presentation. This highlights the need to consider PH when diagnosing MSA/MAA-associated conditions. We recommend MSA/MAA screening for newly diagnosed PH, especially in those with ILD, for early detection and potential immunomodulatory treatment. Further research should explore the link between MSAs/MAAs and PH, and the value of monitoring patients with weak MSA/MAA positivity over time.

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., (© 2024. The Author(s).)

Background: Although several studies have addressed plasma proteomics in heart failure with preserved ejection fraction, limited data are available on the prognostic value of urinary proteomics. The objective of our study was to identify urinary proteins/peptides associated with death and heart failure admission in patients with heart failure with preserved ejection fraction., Methods and Results: The study population included participants enrolled in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). The relationship between urine protein levels and the risk of death or heart failure admission was assessed using Cox regression, in both nonadjusted analyses and adjusting for urine creatinine levels, and the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) score. A total of 426 (12.4%) TOPCAT participants had urinary protein data and were included. There were 40 urinary proteins/peptides significantly associated with death or heart failure admission in nonadjusted analyses, 21 of which were also significant adjusted analyses. Top proteins in the adjusted analysis included ANGPTL2 (angiopoietin-like protein 2) (hazard ratio [HR], 0.5731 [95% CI, 0.47-0.7]; P =3.13E-05), AMY2A (α amylase 2A) (HR, 0.5496 [95% CI, 0.44-0.69]; P =0.0001), and DNASE1 (deoxyribonuclease-1) (HR, 0.5704 [95% CI, 0.46-0.71]; P =0.0002). Higher urinary levels of proteins involved in fibrosis (collagen VI α-1, collagen XV α-1), metabolism (pancreatic α-amylase 2A/B, mannosidase α class 1A member 1), and inflammation (heat shock protein family D member 1, inducible T cell costimulatory ligand) were associated with a lower risk of death or heart failure admission., Conclusions: Our study identifies several novel associations between urinary proteins/peptides and outcomes in heart failure with preserved ejection fraction. Many of these associations are independent of clinical risk scores and may aid in risk stratification in this patient population.

Background: Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization., Methods and Results: The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all-cause death or (2) death or HF-related hospital admission (DHFA). The authors replicated nominally significant associations in the Washington University HF registry (N=1080). Proteins significantly associated with outcomes were the subject of 2-sample Mendelian randomization and colocalization analyses. After correction for multiple testing, 243 and 126 proteins were found to be significantly associated with death and DHFA, respectively. These included small ubiquitin-like modifier 2 (standardized hazard ratio [sHR], 1.56; P <0.0001), growth differentiation factor-15 (sHR, 1.68; P <0.0001) for death, A disintegrin and metalloproteinase with thrombospondin motifs-like protein (sHR, 1.40; P <0.0001), and pulmonary-associated surfactant protein C (sHR, 1.24; P <0.0001) for DHFA. In pathway analyses, top canonical pathways associated with death and DHFA included fibrotic, inflammatory, and coagulation pathways. Genomic analyses provided evidence of nominally significant associations between levels of 6 genetically predicted proteins with DHFA and 11 genetically predicted proteins with death., Conclusions: This study implicates multiple novel proteins in HF and provides preliminary evidence of associations between genetically predicted plasma levels of 17 candidate proteins and the risk for adverse outcomes in human HF.

Background: NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels are variably elevated in heart failure with preserved ejection fraction (HFpEF), even in the presence of increased left ventricular filling pressures. NT-proBNP levels are prognostic in HFpEF and have been used as an inclusion criterion for several recent randomized clinical trials. However, the underlying biologic differences between HFpEF participants with high and low NT-proBNP levels remain to be fully understood., Methods: We measured 4928 proteins using an aptamer-based proteomic assay (SOMAScan) in available plasma samples from 2 cohorts: (1) Participants with HFpEF enrolled in the PHFS (Penn Heart Failure Study; n=253); (2) TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) participants in the Americas (n=218). We assessed the relationship between SOMAScan-derived plasma NT-proBNP and levels of other proteins available in the SOMAScan assay version 4 using robust linear regression, with correction for multiple comparisons, followed by pathway analysis., Results: NT-proBNP levels exhibited prominent proteome-wide associations in PHFS and TOPCAT cohorts. Proteins most strongly associated with NT-proBNP in both cohorts included SVEP1 (sushi, von Willebrand factor type-A, epidermal growth factor, and pentraxin domain containing 1; β TOPCAT =0.539; P <0.0001; β PHFS =0.516; P <0.0001) and ANGPT2 (angiopoietin 2; β TOPCAT =0.571; P <0.0001; β PHFS =0.459; P <0.0001). Canonical pathway analysis demonstrated consistent associations with multiple pathways related to fibrosis and inflammation. These included hepatic fibrosis and inhibition of matrix metalloproteases. Analyses using cut points corresponding to estimated quantitative concentrations of 360 pg/mL (and 480 pg/mL in atrial fibrillation) revealed similar proteomic associations., Conclusions: Circulating NT-proBNP levels exhibit prominent proteomic associations in HFpEF. Our findings suggest that higher NT-proBNP levels in HFpEF are a marker of fibrosis and inflammation. These findings will aid the interpretation of NT-proBNP levels in HFpEF and may guide the selection of participants in future HFpEF clinical trials., Competing Interests: Disclosures Dr Chirinos has recently consulted for Bayer, Sanifit, Fukuda-Denshi, Bristol Myers Squibb, Johnson & Johnson, Edwards Life Sciences, Merck, and the Galway-Mayo Institute of Technology. He received University of Pennsylvania research grants from the National Institutes of Health, Fukuda-Denshi, Bristol Myers Squibb, and Microsoft. He is named as an inventor in a University of Pennsylvania patent for the use of inorganic nitrates/nitrites in Heart Failure With Preserved Ejection Fraction. He has received research device loans from Atcor Medical, Fukuda-Denshi, Uscom, NDD Medical Technologies, Microsoft, and MicroVision Medical. Dr Zamani receives research support from Amgen. He has consulted for Pfizer and Vyaire. Dr Rietzschel has received unrestricted educational grants from Amgen, Merck Sharp & Dohme, AstraZeneca, Sanofi, and Unilever and speakers’ or consultancy fees from Daiichi Sankyo, Novo Nordisk, Boehringer Ingelheim, Servier, Amgen, Sanofi, Novartis, and Teva, all paid directly to Ghent University. He is named as inventor on patent applications for the use of plasma and urine protein biomarkers in heart failure. Dr Richards is supported by grants from Singapore National Medical Research Council and the Health Research Council of New Zealand. He holds the New Zealand Heart Foundation Chair in Cardiovascular Studies. In kind support and research grants are received from Roche Diagnostics, Abbott Laboratories, and Novo Nordisk. He is named on ≈30 cardiovascular biomarker patents. Dr Gill acknowledges support by the British Heart Foundation Centre of Research Excellence at Imperial College London (RE/18/4/34215). The other authors report no conflicts.

Aims: Current heart failure (HF) guidelines recommend to prescribe four drug classes in patients with HF with reduced ejection fraction (HFrEF). A clear challenge exists to adequately implement guideline-directed medical therapy (GDMT) regarding the sequencing of drugs and timely reaching target dose. It is largely unknown how the paradigm shift from a serial and sequential approach for drug therapy to early parallel application of the four drug classes will be executed in daily clinical practice, as well as the reason clinicians may not adhere to new guidelines. We present the design and rationale for the real-world TITRATE-HF study, which aims to assess sequencing strategies for GDMT initiation, dose titration patterns (order and speed), intolerance for GDMT, barriers for implementation, and long-term outcomes in patients with de novo, chronic, and worsening HF., Methods and Results: A total of 4000 patients with HFrEF, HF with mildly reduced ejection fraction, and HF with improved ejection fraction will be enrolled in >40 Dutch centres with a follow-up of at least 3 years. Data collection will include demographics, physical examination and vital parameters, electrocardiogram, laboratory measurements, echocardiogram, medication, and quality of life. Detailed information on titration steps will be collected for the four GDMT drug classes. Information will include date, primary reason for change, and potential intolerances. The primary clinical endpoints are HF-related hospitalizations, HF-related urgent visits with a need for intravenous diuretics, all-cause mortality, and cardiovascular mortality., Conclusions: TITRATE-HF is a real-world multicentre longitudinal registry that will provide unique information on contemporary GDMT implementation, sequencing strategies (order and speed), and prognosis in de novo, worsening, and chronic HF patients., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Obesity is causally related to the development of heart failure with preserved ejection fraction (HFpEF) but complicates the diagnosis and treatment of this disorder. We aimed to determine the relationship between severity of obesity and clinical, echocardiographic and haemodynamic parameters in a large cohort of patients with documented HFpEF., Methods and Results: The REDUCE LAP-HF II trial randomized 626 patients with ejection fraction ≥40% and exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg to atrial shunt or sham procedure. We tested for associations between body mass index (BMI), clinical characteristics, cardiac structural and functional abnormalities, physical limitations, quality of life and outcomes with atrial shunt therapy. Overall, 60.9% of patients had BMI ≥30 kg/m 2 . As the severity of obesity increased, symptoms (Kansas City Cardiomyopathy Questionnaire score) and 6-min walk distance worsened. More severe obesity was associated with lower natriuretic peptide levels despite more cardiac remodelling, higher cardiac filling pressures, and higher cardiac output. Lower cut points for E/e' were needed to identify elevated PCWP in more obese patients. Strain measurements in all four chambers were maintained as BMI increased. Pulmonary vascular resistance at rest and exercise decreased with higher BMI. Obesity was associated with more first and recurrent heart failure events. However, there was no significant interaction between obesity and treatment effects of the atrial shunt., Conclusions: Increasing severity of obesity was associated with greater cardiac remodelling, higher right and left ventricular filling pressures, higher cardiac output and increased subsequent heart failure events. Despite significant obesity, many HFpEF patients have preserved right heart and pulmonary vascular function and thus, may be appropriate candidates for atrial shunt therapy., (© 2023 European Society of Cardiology.)

The Simpson's method is the standard technique to determine left ventricular (LV) ejection fraction (EF) on echocardiography. The large inter-observer variability of measuring LVEF is well documented but not fully understood. A graphical analysis was used to elaborate what contributes to the inter-observer difference. Forty-two cardiologists (32 male, 39 ± 7 years) evaluated the LVEF using the Simpson's method on 15 different echocardiograms (2 and 4 chamber view (2CH/4CH)); the program did not show the result of EF to prevent a bias. End-diastolic (ED) and end-systolic (ES) frames were predefined ensuring measurement at the same time point of the cardiac cycles. After standardization of the LV contour, the differences of the individual contours compared to a reference contour were measured. Also, the spreading of lateral/medial mitral annulus contours and the apex were depicted. A significant spreading of LV-contours was seen with larger contours leading to higher EFs (p < 0.001). Experience did not influence the determination of LVEF. ED-volumes showed more spreading than ES-volumes ((3.6 mm (IQR: 2.6-4.0) vs. 3.4 mm (IQR: 2.8-3.8), p < 0.001). Also, the differences were larger for the 2CH compared to the 4CH (p < 0.001). Variability was significantly larger for lateral than septal wall (p < 0.001) as well as the anterior compared to the inferior wall (p < 0.001). There was a relevant scattering of the apex and medial/ lateral mitral annulus ring. There was a large variability of LV-volumes and LVEF as well as position of mitral valve ring and apex. There were global differences (apical 2CH or 4CH), regional aspects (LV walls) and temporal factors (ED vs. ES). Thus, multiple factors contributed to the large variability.Trial registration: The study was registered at "Netherlands Trial Register" ( www.trialregister.nl ; study number: NL5131)., (© 2023. The Author(s).)

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., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: It is hypothesized that inflammation leads to heart failure. Results from observational studies thus far have been inconsistent and it is unclear whether inflammation is causally associated with new-onset heart failure. Mendelian randomization analyses are less prone to biases common in observational studies such as reverse causation and unmeasured confounding. The aim of this study was to investigate the causal relation between various inflammatory biomarkers with risk of new-onset heart failure by using a two-sample Mendelian randomization approach., Methods: Ten inflammatory biomarkers with available genome-wide association studies (GWAS) among individuals of European ancestry were identified and included C-reactive protein (CRP), immunoglobulin E, tumour necrosis factor (TNF), toll-like receptor 4, interleukin 1 receptor antagonist, interleukin 2 receptor subunit α, interleukin 6 receptor subunit α, interleukin 16, 17 and 18. For the associations between the identified SNPs and heart failure, we used the largest GWAS meta-analysis performed by the Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium with 47 309 participants with heart failure and 930 014 controls. For our main analyses, we used the inverse-variance weighted method., Results: We included 63 SNPs. CRP, TNF, interleukin 2, 16 and 18 were not associated with heart failure with odds ratios (ORs) of 1.01 [95% confidence interval (95% CI: 0.94-1.09), 1.11 (95% CI: 0.80-1.48), 0.97 (95% CI: 0.93-1.02), 0.99 (95% CI: 0.96-1.03) and 1.01 (95% CI: 0.97-1.06), respectively. The other biomarkers were also not associated with the risk of heart failure and suffered from weak instrument bias., Conclusion: This Mendelian randomization study could not determine a causal relationship between inflammation and risk of heart failure. However, some biomarkers suffered from weak instrument bias., (Copyright © 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: The TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) suggested clinical benefits of spironolactone treatment among patients with heart failure with preserved ejection fraction enrolled in the Americas. However, a comprehensive assessment of biologic pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction has not been performed., Methods: We conducted aptamer-based proteomic analysis utilizing 5284 modified aptamers to 4928 unique proteins on plasma samples from TOPCAT participants from the Americas (n=164 subjects with paired samples at baseline and 1 year) to identify proteins and pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction. Mean percentage change from baseline was calculated for each protein. Additionally, we conducted pathway analysis of proteins altered by spironolactone., Results: Spironolactone therapy was associated with proteome-wide significant changes in 7 proteins. Among these, CARD18 (caspase recruitment domain-containing protein 18), PKD2 (polycystin 2), and PSG2 (pregnancy-specific glycoprotein 2) were upregulated, whereas HGF (hepatic growth factor), PLTP (phospholipid transfer protein), IGF2R (insulin growth factor 2 receptor), and SWP70 (switch-associated protein 70) were downregulated. CARD18, a caspase-1 inhibitor, was the most upregulated protein by spironolactone (-0.5% with placebo versus +66.5% with spironolactone, P <0.0001). The top canonical pathways that were significantly associated with spironolactone were apelin signaling, stellate cell activation, glycoprotein 6 signaling, atherosclerosis signaling, liver X receptor activation, and farnesoid X receptor activation. Among the top pathways, collagens were a consistent theme that increased in patients receiving placebo but decreased in patients randomized to spironolactone., Conclusions: Proteomic analysis in the TOPCAT trial revealed proteins and pathways altered by spironolactone, including the caspase inhibitor CARD18 and multiple pathways that involved collagens. In addition to effects on fibrosis, our studies suggest potential antiapoptotic effects of spironolactone in heart failure with preserved ejection fraction, a hypothesis that merits further exploration.

This study aimed to evaluate the diagnostic performance of echocardiographic markers of heart failure with preserved ejection fraction (HFpEF) and left ventricular diastolic dysfunction (LVDD) in comparison with the gold standard of cardiac catheterization. Diagnosing HFpEF is challenging, as symptoms are non-specific and often absent at rest. A clear need exists for sensitive echocardiographic markers to diagnose HFpEF. We systematically searched for studies testing the diagnostic value of novel echocardiographic markers for HFpEF and LVDD. Two investigators independently reviewed the studies and assessed the risk of bias. Results were meta-analysed when four or more studies reported a similar diagnostic measure. Of 353 studies, 20 fulfilled the eligibility criteria. The risk of bias was high especially in the patients' selection domain. The highest diagnostic performance was demonstrated by a multivariable model combining echocardiographic, clinical and arterial function markers with an area under the curve of 0.95 (95% CI, 0.89-0.98). A meta-analysis of four studies indicated a reasonable diagnostic performance for left atrial strain with an AUC of 0.83 (0.70-0.95), a specificity of 93% (95% CI, 90-97%) and a sensitivity of 77% (95% CI, 59-96%). Moreover, the addition of exercise E/e' improved the sensitivity of HFpEF diagnostic algorithms up to 90%, compared with 60 and 34% of guidelines alone. Despite the heterogeneity of the included studies, this review supported the current multivariable-based approach for the diagnosis of HFpEF and LVDD and showed a potential diagnostic role for exercise echocardiography and left atrial strain. Larger well-designed studies are needed to evaluate the incremental value of novel diagnostic tools to current diagnostic algorithms., (© 2020. The Author(s).)

We investigated the prospective associations of body composition with cardiac structure and function and explored effect modification by sex and whether inflammation was a mediator in these associations. Total body (BF), trunk (TF) and leg fat (LF), and total lean mass (LM) were measured at baseline by a whole body DXA scan. Inflammatory biomarkers and echocardiographic measures were determined both at baseline and follow-up in the Hoorn Study (n = 321). We performed linear regression analyses with body composition measures as determinant and left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI) or left atrial volume index (LAVI) at follow-up as outcome. Additionally, we performed mediation analysis using inflammation at follow-up as mediator. The study population was 67.7 ± 5.2 years and 50% were female. After adjustment, BF, TF and LF, and LM were associated with LVMI with regression coefficients of 2.9 (0.8; 5.1)g/m 2.7 , 2.3 (0.6; 4.0)g/m 2.7 , 2.0 (0.04; 4.0)g/m 2.7 and - 2.9 (- 5.1; - 0.7)g/m 2.7 . Body composition measures were not associated with LVEF or LAVI. These associations were not modified by sex or mediated by inflammation. Body composition could play a role in the pathophysiology of LV hypertrophy. Future research should focus on sex differences in regional adiposity in relation with diastolic dysfunction., (© 2021. The Author(s).)

Aims: Heart failure (HF) is common in both men and women, yet disease pathophysiology, presentation, and progression differ between sexes. Studies addressing whether biomarkers predict new onset HF sex-specifically are scarce. This study therefore aims to test the sex-specificity of 252 protein biomarkers for new-onset HF., Methods and Results: A matched case-control design in patients selected from cohorts within the HOMAGE consortium was used. Cases (new-onset HF, n = 562) and controls (n = 780) were matched for cohort (PREDICTOR, HEALTH-ABC, & PROSPER), follow-up time (defined as time from entry to incident HF), and age. Incident HF was defined as first hospitalization for HF. Targeted plasma proteins (n = 252) were measured using Proximity Extension Assay technology from O-link. To look for sex differences for new onset HF, we adjusted for cohort, age, and baseline clinical parameters. At baseline, women had a biomarker profile reflecting activated metabolism and immune responses. However, none of the biomarkers had a significant interaction with sex in predicting new onset HF, but four biomarkers had a trend towards sex-specificity (P < 0.013). E-selectin and interleukin 1 receptor antagonist were more female-specific, whereas IL17A and CHIT1 tended to be male sex-specific for incident HF., Conclusions: The majority of biomarkers associated with incident HF did not significantly differ between women and men, despite clear differences in biomarkers at baseline., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)