Christian Knackstedt

Background: Diagnosis of heart failure with preserved ejection fraction (HFpEF) using the HFA-PEFF and H2FPEF scores remains challenging in clinical practice, and relies on echocardiographic assessment. We aimed to determine whether diagnostic scoring based on automated deep learning interpretation of echocardiograms performs similar to manual measurements in diagnosing HFpEF. Methods: We analyzed echocardiograms using an automated deep learning algorithm and manually in three cohorts: a test cohort (102 HFpEF patients diagnosed by right heart catheterization and echocardiography), an ambulatory validation cohort (129 HFpEF patients), and a diagnostic validation cohort (n = 427, of which 182 HFpEF and 245 non-HFpEF patients). We evaluated correlations between automated and manual HFA-PEFF and H2FPEF scores across cohorts, their correlation with pulmonary capillary wedge pressures (PCWP), and compared diagnostic accuracy using the area-under-the-curve (AUC). Results: Automated and manual measurements showed good agreement across cohorts, with good correlations between HFA-PEFF (0.78-0.86) and H2FPEF (0.96-0.98) scores and similar correlations with PCWP. One in five patients with high-likelihood HFpEF based on manual HFA-PEFF scores were classified as intermediate-likelihood by automated scores due to lower estimated left atrial volumes, without consistent interaction with atrial fibrillation. AUCs for automated HFA-PEFF and H2FPEF scores did not consistently differ from manual scores (0.70 [95% confidence interval (CI): 0.66-0.74] vs. 0.71 [95% CI: 0.66-0.75], and 0.78 [95% CI: 0.73-0.82] vs. 0.75 [95% CI: 0.71-0.80], respectively). Conclusion: HFA-PEFF and H2FPEF scores based on automated and manual echocardiographic analysis showed similar diagnostic accuracy, suggesting automated HFpEF diagnosis using deep learning analysis of echocardiograms is feasible.

Background: Cardiac involvement is the major determinant of mortality in variant TTR amyloidosis (ATTRv). Treatment options have recently become available, which make early diagnosis important. Several imaging modalities for screening are proposed including bone scintigraphy, conventional, and strain echocardiography but data on their relative value is limited in this population. Objectives: To investigate the value of left ventricular global longitudinal strain (LV-GLS) for screening for cardiac involvement in a population of transthyretin (TTR) pathogenic variant carriers. Methods: Fifty-three TTR pathogenic variant carriers from two Dutch academic hospitals underwent transthoracic echocardiography (TTE) and bone scintigraphy as part of routine out-patient care to assess cardiac involvement. LV-GLS was measured by two blinded reviewers. Abnormalities in LV-GLS (cut-off − 21.5%) and other TTE parameters were evaluated in bone scintigraphy positive (≥ grade 1) and negative cases. Results: Carriers with a positive bone scintigraphy ( n = 20/53) were 16 years older than those with a negative scan ( n = 33/53). In 17 out of 20 (85%) of patients with a positive bone scintigraphy, LV-GLS was abnormal. When bone scintigraphy was negative, LV-GLS was abnormal in 11 cases (38%). Although most of these patients had no obvious alternative explanation for the reduced LV-GLS, the clinical significance of this finding remains uncertain. LV-GLS as a single echo parameter was equally sensitive to detect an abnormal bone scintigraphy versus all other TTE parameters together. Conclusions: LV-GLS and bone scintigraphy provided complementary information in TTR pathogenic variant carriers. Discordant findings between both modalities warrant further evaluation, as abnormal LV-GLS may reflect early ATTRv-related changes but is not disease-specific. These findings are exploratory and hypothesis-generating and warrant confirmation in prospective studies incorporating additional reference standards.LV-GLS was the most sensitive single echo parameter, making it useful for repeated assessment in this population.

1. Hypertrophic cardiomyopathy (HCM) is a complex and multifactorial myocardial disorder characterized by primary left ventricular hypertrophy not caused by any other reason.1 It is estimated that ...

Aims: A previous trial of intravenous immunoglobulin therapy (IVIg) added to guideline-directed medical therapy (GDMT) in patients with dilated cardiomyopathy (DCM) and cardiac parvovirus-B19 (B19 V) persistence showed no improvement of cardiac function at 6 months follow-up. We investigated whether IVIg confers long-term clinical benefits and analysed its molecular and cellular effects in cardiac tissue to elucidate the immunomodulatory mechanisms underlying the observed long-term clinical improvement. Methods: Fifty patients with DCM and cardiac B19 V were blindly randomized to receive either IVIg (n = 26; 2 g/kg/day over 4 days) or placebo (n = 24). The composite clinical endpoint—cardiac death, heart failure hospitalization, and life-threatening arrhythmia—was assessed after a median follow-up of 6.8 (5.6–10.3) years. To investigate IVIg-associated molecular changes in the heart, single-nuclear RNA sequencing (snRNA-seq) sequencing on endomyocardial biopsies (EMB) obtained at baseline (prior to treatment) and at 6 months after randomization was performed. Results: The IVIg group experienced fewer composite endpoint events (n = 1/26) than the placebo group (8/24; P = .0075). Comparison of baseline and 6-month EMBs by snRNA-seq showed that IVIg treatment reduced cardiac monocyte infiltration and, unlike placebo, prevented the expansion of injured cardiomyocytes. IVIg induced transcriptomic reprogramming across immune cells, fibroblasts, and cardiomyocytes, including diminished myeloid-to-fibroblast signalling with reduced TGFβ activity, decreased pro-fibrotic and pro-inflammatory pathways and metabolic shifts in cardiomyocytes characterized by enhanced oxidative phosphorylation. Conclusion: In patients with DCM and cardiac B19 V persistence, IVIg added to GDMT correlated with improved long-term clinical outcome. IVIg may attenuate myeloid-driven fibrosis formation and mitigate cardiomyocyte deterioration.

Patients with heart failure and preserved ejection fraction (HFpEF) experience significant exercise intolerance, yet its underlying mechanisms remain poorly defined and are multifactorial. Iron deficiency (ID) occurs frequently in HFpEF and may contribute to exercise impairment. This study evaluated mitochondrial oxidative muscle metabolism in HFpEF using in vivo ³¹phosphorus magnetic resonance spectroscopy (³¹P-MRS) employing two exercise protocols, and assessed whether ID influences exercise energetics. In this parallel analysis of prospective studies at two sites, patients with HFpEF and control individuals performed either isometric exercise (isolated leg protocol) or dynamic exercise (cardiopulmonary protocol) with concomitant phosphocreatine recovery assessment using in vivo ³¹P-MRS. Associations between clinical factors and oxidative metabolism were evaluated. ID was defined as ferritin P =. 01). Patients with HFpEF exhibit impaired whole-muscle oxidative capacity of skeletal muscle, as shown by two different ³¹P-MRS protocols with upper leg measurements, independent of ID status. NTR6605, NTR7297 (https://onderzoekmetmensen.nl/nl/trial/55673); NCT05750940 (https://clinicaltrials.gov/study/NCT05750940).

Cardiac fibrosis is a key disease hallmark of dilated cardiomyopathy (DCM) and is associated with a risk of malignant arrhythmias and sudden cardiac death. Fibrosis can be the earliest sign of disease in asymptomatic family members carrying pathogenic variants, making timely recognition essential. Although echocardiography is often used for family screening, conventional echocardiography cannot assess myocardial tissue characteristics such as fibrosis. Cardiac magnetic resonance imaging (CMR), the reference standard for detecting myocardial fibrosis, provides tissue characterization but is challenging to be used as a first-line screening for all at-risk family members. Shear wave elastography (SWE) using high-frame rate echocardiography is an emerging technique that enables assessment of myocardial stiffness as a surrogate for fibrosis. The VISUALIZE-DCM trial is an investigator-initiated, single-center prospective study that evaluates SWE as a triage tool for CMR to detect myocardial fibrosis, and to determine whether increased myocardial stiffness is an early feature of genetic DCM. In this study, both naturally occurring and acoustic generated shear wave speeds (SWS) are assessed using high-frame rate imaging. Natural shear waves arise during valvular closure, whereas generated shear waves are induced by the acoustic radiation force. Myocardial stiffness measurements derived from SWS will be obtained in patients with established DCM, their at-risk family members, and healthy volunteers. SWE findings will be compared with fibrosis patterns on CMR, evaluated for their ability to detect early disease development in relatives, and contrasted with reference values from healthy controls to determine their potential clinical utility in DCM screening and risk stratification.

Background Patients with hypertrophic cardiomyopathy (HCM) often reduce their physical activity due to concerns about sudden cardiac death. However, objective data on activity patterns in HCM, particularly in relation to clinical phenotype and quality of life (QoL), remain limited. Methods We assessed physical activity using 7-day accelerometry in 203 patients with HCM and 37 genotype-positive, phenotype-negative (G+/P−) individuals. Outcomes included daily step counts, time spent in moderate-to-vigorous physical activity (MVPA) and sedentariness. QoL was measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQoL 5-domain 5-level (EQ-5D-5L). Results HCM patients took fewer steps/day (5254 vs 6573), engaged in less MVPA (3.4% vs 4.5% of the day) and were more often sedentary (61% vs 35% spending >80% of the day sedentary) compared with G+/P− controls (all pConclusions Objectively measured physical activity was significantly lower in HCM patients compared with G+/P− individuals, particularly among those with symptoms, obstruction or obesity. Even modestly higher daily step counts were associated with better QoL, highlighting the relevance of individualised, phenotype-informed exercise counselling in HCM.

Aims: Comorbidities play an important role in heart failure (HF) with preserved ejection fraction (HFpEF). Still, current guidelines lack clear directives for routine comorbidity screening and are primarily based on HF with reduced ejection fraction populations. This study evaluates the diagnostic yield of standardized routine workup for comorbidities in HFpEF. The goal is to provide clinicians with actionable insights to refine strategies for screening and managing HFpEF patients. Methods and results: This single-centre prospective observational cohort study included patients diagnosed with HFpEF via a specialized outpatient clinic and evaluated the diagnostic yield of standardized diagnostic workup for comorbidities, including laboratory testing, sleep apnoea screening, 24 h Holter monitoring, spirometry, exercise testing, and 6 min walk test. A total of 501 HFpEF patients (age 75 ± 7 years, 67% female) were included. Before diagnostic workup, a median of three [2–5] comorbidities was known, and one additional comorbidity was diagnosed during standardized workup, most commonly sleep apnoea (33%) and iron deficiency (35%). Overall, the most prevalent comorbidities were hypertension (74%), sleep apnoea (52%), atrial fibrillation (50%), iron deficiency (49%), and obesity (45%). Pre-existing comorbidities did not receive optimal guideline-directed therapy, specifically diabetes (23%), hypercholesterolaemia (36%), and obesity (45%). Conclusion: This study highlights the value of routine comorbidity screening in HFpEF, identifying one new comorbidity per patient on top of three pre-existing conditions, most commonly sleep apnoea or iron deficiency. Treatment of existing comorbidities was often suboptimal. Systematic screening not only improves the detection of undiagnosed conditions but also enables personalized and effective comorbidity management.

Background: Most patients with heart failure with preserved ejection fraction (HFpEF) have a metabolic phenotype in which comorbidities including diabetes mellitus play an important role. Factors related to impaired glucose metabolism, such as kidney disease, may contribute to adverse clinical events. Albuminuria is an early marker of kidney disease. We assessed the prevalence of impaired glucose metabolism and albuminuria in HFpEF over time, and evaluated its prognostic implications. Methods: Consecutive patients referred to our outpatient clinic and diagnosed with HFpEF between March 2015–November 2023 were included in this study. Patients with type 1 diabetes were excluded. Patients were stratified according to baseline glucose metabolism status (DM + for prediabetes and diabetes, or DM−) and albuminuria status (ALB+ or ALB− for albuminuria > 3.0 mg/mmol and normoalbuminuria, respectively). The primary outcome was a composite of HF hospitalizations (HFH) and all-cause mortality, and was analysed using multivariable-adjusted Cox-regression models. Results: Among 332 patients with HFpEF (median age 77 years; 67% female), 121 (36.4%) were classified as DM−/ALB−, 106 (31.9%) as DM+ /ALB−, 44 (13.3%) as DM−/ALB+, and 61 (18.4%) as DM+ /ALB+. Both baseline DM and ALB were independently associated with the primary outcome after approximately 3 years: adjusted hazard ratio (aHR) 1.93; 95% confidence interval (CI) 1.25–2.97 and 1.58; 95%CI 1.04–2.41, respectively. Patients in the DM+ /ALB+ group showed the highest risk (aHR 2.85; 95%CI 1.57–5.15). After one year, DM/ALB status was re-evaluated in 250 (75%) patients. New DM+ and ALB+ incidence was 3.9% and 22%in those at risk, respectively. Patients particularly changed ALB groups compared to baseline (n = 63, 25.2%); 27 (10.8%) patients recovered from albuminuria. At 3 years follow-up, the primary outcome mainly occurred in patients who consistently showed albuminuria (27.1%) or who recovered from albuminuria (22.2%), and less so in patients who developed albuminuria after one year (13.9%) or who remained free of albuminuria (8.6%) (p = 0.008). Conclusions: DM and albuminuria are prevalent in HFpEF at baseline, and re-evaluation one year later still reveals new diagnoses. Both factors are independently associated with adverse outcomes. Albuminuria at any time point remains predictive of adverse outcomes in HFpEF. Graphical Research insights: What is currently known about this topic?: Diabetes mellitus is an important cardiovascular risk factor in patients with HFpEF, contributing to disease progression and worse outcomes. Albuminuria is a prognostic marker in heart failure patients and more prevalent in patients with diabetes What is the key research question?: What is prevalence of impaired glucose metabolism and albuminuria in HFpEF over time and how does this translate to prognosis? What is new?: Both DM and albuminuria each independently associated with worse prognosis in HFpEF. Screening 1 year after HFpEF diagnosis yielded incidence rates of 3.9% and 10.8% for DM and prediabetes, respectively, and 22% for albuminuria. Albuminuria at any time point appeared prognostic in HFpEF, also when albuminuria recovered How might this study influence clinical practice?: Intermittent screening of HFpEF patients for abnormal glucose metabolism and albuminuria is warranted to optimize risk management

Background: To assess the psychometric properties (content validity, reliability and construct validity) of generic and disease-specific health-related quality of life (HRQoL) instruments in patients with hypertrophic cardiomyopathy (HCM) and genotype-positive, phenotype-negative (G+/P−) individuals. Methods: As part of the multicentre, observational AFFECT-HCM study, HRQoL was measured using the generic EuroQoL-5 Dimension-5 Level (EQ-5D-5L) questionnaire, the Visual Analogue Scale (EQ VAS) and the disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ). The study included G+/P− individuals and HCM patients. EQ-5D-5L profiles were translated into EQ-5D values (utilities) using the Dutch value set. All instruments were evaluated regarding their general characteristics and health dimensions (content validity). Reliability was assessed using internal consistency (Cronbach’s alpha), response rate, floor/ceiling effects (percentage scoring highest/lowest), correlation and level of agreement between instruments (using Bland-Altman plots). Construct validity was assessed using the known-groups method to identify expected differences between relevant groups. Results: A total of 393 HCM patients and 78 G+/P− individuals were included in the psychometric assessment. Mean EQ-5D value in G+/P− individuals was 0.90 (81 EQ VAS, 93 KCCQ) and in HCM patients 0.84 (75 EQ VAS, 78 KCCQ). Ceiling effects were highest for EQ-5D values (51% in G+P; 32% in HCM), followed by the KCCQ (38% in G+P−; 12% in HCM) and the EQ VAS (8% in G+P−; 5% in HCM). KCCQ and EQ-5D values had the highest correlation (Spearman’s ρ=0.77) and showed good overall agreement according to the Bland-Altman plots. In HCM, EQ-5D values showed a slightly biased pattern with EQ-5D values scoring higher than the KCCQ. The KCCQ discriminated more nuances between relevant groups. Conclusions: Due to its simplicity and good overall agreement with the KCCQ—which showed slightly better discrimination—we propose from our data that the EQ-5D-5L is a suitable instrument for the HRQoL assessment in clinical practice in patients with HCM.