Characterization and Mortality Risk of Impaired Left Ventricular Filling in COPD.

BACKGROUND: In COPD, impaired left ventricular (LV) filling might be associated with coexisting HFpEF or due to reduced pulmonary venous return indicated by small LV size. We investigate the all-cause mortality associated with small LV or HFpEF and clinical features discriminating between both patterns of impaired LV filling. METHODS: We performed transthoracic echocardiography (TTE) in patients with stable COPD from the COSYCONET cohort to define small LV as LVEDD below the normal range and HFpEF features according to recommendations of the European Society of Cardiology. We assessed the E/A and E/e' ratios, NT-pro-BNP, hs-Troponin I, FEV1, RV, DLCo, and discriminated patients with small LV from those with HFpEF features or no relevant cardiac dysfunction as per TTE (normalTTE). The primary outcome was all-cause mortality after four and a half year. RESULTS: In 1752 patients with COPD, the frequency of small LV, HFpEF-features, and normalTTE was 8%, 16%, and 45%, respectively. Patients with small LV or HFpEF features had higher all-cause mortality rates than patients with normalTTE, HR: 2.75 (95% CI: [1.54 - 4.89]) and 2.16 (95% CI: [1.30 - 3.61]), respectively. Small LV remained an independent predictor of all-cause mortality after adjusting for confounders including exacerbation frequency and measures of RV, DLCo, or FEV1. Compared to normalTTE, patients with small LV had reduced LV filling, as indicated by lowered E/A. Yet in contrast to patients with HFpEF-features, patients with small LV had normal LV filling pressure (E/e') and lower levels of NT-pro-BNP and hs-Troponin I. CONCLUSION: In COPD, both small LV and HFpEF-features are associated with increased all-cause mortality and represent two distinct patterns of impaired LV filling This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Elevated Baseline Mean Corpuscular Volume Predicts the Development of Severe Hematologic Toxicity After 177Lu-DOTATATE Therapy.

177Lu-DOTATATE is an effective second-line treatment for metastatic or nonresectable neuroendocrine tumors. This treatment can result in hematologic severe adverse reactions (SARs). Preemptive identification of patients at risk of SARs could mitigate this risk and improve treatment safety and outcomes. Methods: Demographic and oncologic history, pretreatment laboratory values, and SAR frequency were obtained for 126 sequential patients treated with 177Lu-DOTATATE. Univariable and multivariable logistic regression models identified factors correlating with SARs. Results: Relative pretreatment anemia, leukopenia, thrombocytopenia, and elevated mean corpuscular volume (MCV) were significantly correlated with SARs, with an odds ratio of 16 (95% CI, 5-65) in patients with an MCV greater than 95 fL. Conclusion: Pretreatment bone marrow dyscrasias, including an MCV greater than 95 fL, may predict patients at risk for SARs when treated with 177Lu-DOTATATE. Further study is needed to determine whether the risks of SARs outweigh the benefit in these patients.

Expiratory Venous Volume and Arterial Tortuosity are Associated with Disease Severity and Mortality Risk in Patients with COPD: Results from COSYCONET.

Purpose: The aim of this study was to evaluate the association between computed tomography (CT) quantitative pulmonary vessel morphology and lung function, disease severity, and mortality risk in patients with chronic obstructive pulmonary disease (COPD). Patients and Methods: Participants of the prospective nationwide COSYCONET cohort study with paired inspiratory-expiratory CT were included. Fully automatic software, developed in-house, segmented arterial and venous pulmonary vessels and quantified volume and tortuosity on inspiratory and expiratory scans. The association between vessel volume normalised to lung volume and tortuosity versus lung function (forced expiratory volume in 1 sec [FEV1]), air trapping (residual volume to total lung capacity ratio [RV/TLC]), transfer factor for carbon monoxide (TLCO), disease severity in terms of Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D, and mortality were analysed by linear, logistic or Cox proportional hazard regression. Results: Complete data were available from 138 patients (39% female, mean age 65 years). FEV1, RV/TLC and TLCO, all as % predicted, were significantly (p < 0.05 each) associated with expiratory vessel characteristics, predominantly venous volume and arterial tortuosity. Associations with inspiratory vessel characteristics were absent or negligible. The patterns were similar for relationships between GOLD D and mortality with vessel characteristics. Expiratory venous volume was an independent predictor of mortality, in addition to FEV1. Conclusion: By using automated software in patients with COPD, clinically relevant information on pulmonary vasculature can be extracted from expiratory CT scans (although not inspiratory scans); in particular, expiratory pulmonary venous volume predicted mortality. Trial Registration: NCT01245933.

Association of baseline and longitudinal changes in insulin-like growth factor-binding protein-7 with the risk of incident heart failure: Data from the PREVEND study.

AIM: Senescence is a major risk factor for heart failure (HF), and insulin-like growth factor-binding protein-7 (IGFBP7) has been identified as an important senescence-inducing factor. The aim of this study was to examine the value of baseline and repeat IGFBP7 measurements in predicting future HF among community-dwelling Dutch adults from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study. METHODS AND RESULTS: Individuals without prevalent HF who attended PREVEND visits 2 and 4 median of 5.1 years apart (25th-75th percentile, 4.9-5.2) with measurements of IGFBP7 were included. We used Cox proportional hazards models to investigate the association between IGFBP7 and HF incidence. A total of 6125 participants attending visit 2 (mean ± standard deviation [SD] age 53.1 ± 12.2 years; 3151 [51.4%] men) were followed for a median of 8.4 (7.8-8.9) years, and 194 participants (3.2%) developed incident HF. Median baseline IGFBP7 concentration was 87.0 (75.1-97.3) ng/ml, and baseline IGFBP7 levels were significantly associated with risk for incident HF (HF risk factors adjusted hazard ratio [HR] per 1 SD change in log-transformed IGFBP7: 1.22, 95% confidence interval [CI] 1.03-1.46). Baseline IGFBP7 was also significantly associated with incident HF in individuals with N-terminal pro-B-type natriuretic peptide <125 ng/L. Among 3879 participants attending both visits 2 and 4 (mean ± SD age 57.5 ± 11.3 years; 1952 [50.3%] men), 93 individuals developed HF (after visit 4) during a median follow-up of 3.2 (2.8-3.9) years. Median increase in IGFBP7 concentration between visits was 0.68 (-7.09 to 8.36) ng/ml, and changes in IGFBP7 levels were significantly associated with risk for incident HF (HF risk factors adjusted HR per 1 SD change in log-transformed IGFBP7: 1.68, 95% CI 1.19-2.36). CONCLUSIONS: Both baseline as well as repeat IGFBP7 measurements provide information about the risk of developing HF.

Effects of dapagliflozin according to QRS duration across the spectrum of left ventricular ejection fraction: An analysis of DAPA-HF and DELIVER.

AIMS: The primary aim was to evaluate the effect of dapagliflozin according to QRS duration across the spectrum of left ventricular ejection fraction (LVEF), given that prolongation of QRS duration is associated with less favourable ventricular remodelling with pharmacological therapy and worse outcomes. METHODS AND RESULTS: A pooled analysis of the DAPA-HF and DELIVER trials, excluding patients with a paced rhythm and cardiac resynchronization therapy. Overall, 4008 patients had heart failure (HF) with reduced ejection fraction (HFrEF), and 5816 had HF with mildly reduced/preserved ejection fraction (HFmrEF/HFpEF). QRS duration was <120 ms in 7039 patients (71.7%), 120-149 ms in 1725 (17.6%), and ≥150 ms in 1060 patients (10.8%). The median follow-up time was 23 months. The rate of the primary composite outcome of cardiovascular death or worsening HF was 9.2 (95% confidence interval [CI] 8.7-9.7), 14.3 (13.0-15.7), and 15.9 (14.1-17.9) per 100 patient-years in the <120, 120-149, and ≥150 ms groups, respectively. This gradient in event rates was observed both in HFrEF and HFmrEF/HFpEF. Dapagliflozin, compared with placebo, reduced the risk of the primary outcome consistently across the QRS duration subgroups (hazard ratio [95% CI] 0.75 [0.67-0.85], 0.79 [0.65-0.96], and 0.89 [0.70-1.13] in the <120, 120-149, and ≥150 ms groups, respectively; p for interaction = 0.28). The effect of dapagliflozin on the primary outcome was consistent across the QRS duration regardless of HF phenotype that is, HFrEF or HFmrEF/HFpEF. CONCLUSIONS: Prolongation of QRS duration is associated with worse outcomes irrespective of HF phenotype. Dapagliflozin reduced the risk of the primary outcome, regardless of QRS duration, in DAPA-HF and DELIVER.

Proteomic biomarkers related to obesity in heart failure with reduced ejection fraction and their associations with outcome.

OBJECTIVE: Heart failure (HF) pathophysiology in patients with obesity may be distinct. To study these features, we identified obesity-related biomarkers from 4210 circulating proteins in patients with HF with reduced ejection fraction (HFrEF) and examined associations of these proteins with HF prognosis and biological mechanisms. METHODS: In 373 patients with trimonthly blood sampling during a median follow-up of 2.1 (25th-75th percentile: 1.1-2.6) years, we applied an aptamer-based multiplex approach measuring 4210 proteins in baseline samples and the last two samples before study end. Associations between obesity (BMI > 30 kg/m2) and baseline protein levels were analyzed. Subsequently, associations of serially measured obesity-related proteins with biological mechanisms and the primary endpoint (PEP; composite of cardiovascular mortality, HF hospitalization, left ventricular assist device implantation, and heart transplantation) were examined. RESULTS: Obesity was identified in 26% (96/373) of patients. A total of 30% (112/373) experienced a PEP (with obesity: 26% [25/96] vs. without obesity: 31% [87/277]). A total of 141/4210 proteins were linked to obesity, reflecting mechanisms of neuron projection development, cell adhesion, and muscle cell migration. A total of 50/141 proteins were associated with the PEP, of which 12 proteins related to atherosclerosis or hypertrophy provided prognostic information beyond clinical characteristics, N-terminal pro-B-type natriuretic peptide, and high-sensitivity troponin T. CONCLUSIONS: Patients with HFrEF and obesity show distinct proteomic profiles compared to patients with HFrEF without obesity. Obesity-related proteins are independently associated with HF outcome. These proteins carry potential to improve management of obesity-related HF and could be leads for future research.

Midregional Proatrial Natriuretic Peptide (MRproANP) is associated with vertebral fractures and low bone density in patients with chronic obstructive pulmonary disease (COPD).

BACKGROUND: Patients with COPD are often affected by loss of bone mineral density (BMD) and osteoporotic fractures. Natriuretic peptides (NP) are known as cardiac markers, but have also been linked to fragility-associated fractures in the elderly. As their functions include regulation of fluid and mineral balance, they also might affect bone metabolism, particularly in systemic disorders such as COPD. RESEARCH QUESTION: We investigated the association between NP serum levels, vertebral fractures and BMD assessed by chest computed tomography (CT) in patients with COPD. METHODS: Participants of the COSYCONET cohort with CT scans were included. Mean vertebral bone density on CT (BMD-CT) as a risk factor for osteoporosis was assessed at the level of TH12 (AI-Rad Companion), and vertebral compression fractures were visually quantified by two readers. Their relationship with N-terminal pro-B-type natriuretic peptide (NT-proBNP), Mid-regional pro-atrial natriuretic peptide (MRproANP) and Midregional pro-adrenomedullin (MRproADM) was determined using group comparisons and multivariable analyses. RESULTS: Among 418 participants (58% male, median age 64 years, FEV1 59.6% predicted), vertebral fractures in TH12 were found in 76 patients (18.1%). Compared to patients without fractures, these had elevated serum levels (p ≤ 0.005) of MRproANP and MRproADM. Using optimal cut-off values in multiple logistic regression analyses, MRproANP levels ≥ 65 nmol/l (OR 2.34; p = 0.011) and age (p = 0.009) were the only significant predictors of fractures after adjustment for sex, BMI, smoking status, FEV1% predicted, SGRQ Activity score, daily physical activity, oral corticosteroids, the diagnosis of cardiac disease, and renal impairment. Correspondingly, MRproANP (p < 0.001), age (p = 0.055), SGRQ Activity score (p = 0.061) and active smoking (p = 0.025) were associated with TH12 vertebral density. INTERPRETATION: MRproANP was a marker for osteoporotic vertebral fractures in our COPD patients from the COSYCONET cohort. Its association with reduced vertebral BMD on CT and its known modulating effects on fluid and ion balance are suggestive of direct effects on bone mineralization. TRIAL REGISTRATION: ClinicalTrials.gov NCT01245933, Date of registration: 18 November 2010.

Clinical Significance of Exercise Pulmonary Hypertension With a Negative Diastolic Stress Test for Suspected Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Half of patients with heart failure with preserved ejection fraction (HFpEF) remain undiagnosed by resting evaluation alone. Therefore, exercise testing is proposed. The diastolic stress test (DST), however, has limited sensitivity. We aimed to determine the clinical significance of adding the mean pulmonary artery pressure over cardiac output (mPAP/CO) slope to the DST in suspected HFpEF. METHODS AND RESULTS: In this prospective cohort study, consecutive patients (n=1936) with suspected HFpEF underwent exercise echocardiography with simultaneous respiratory gas analysis. These patients were stratified by exercise E over e' (exE/e') and mPAP/CO slope, and peak oxygen uptake, natriuretic peptides (NT-proBNP [N-terminal pro-B-type natriuretic peptide]), and score-based HFpEF likelihood were compared. Twenty-two percent of patients (n=428) had exE/e'<15 despite a mPAP/CO slope>3 mm Hg/L per min, 24% (n=464) had a positive DST (exE/e'≥15), and 54% (n=1044) had a normal DST and slope. Percentage of predicted oxygen uptake was similar in the group with exE/e'<15 but high mPAP/CO slope and the positive DST group (-2% [-5% to +1%]), yet worse than in those with normal DST and slope (-12% [-14% to -9%]). Patients with exE/e'<15 but a high slope had NT-proBNP levels and H2FPEF (heavy, hypertensive, atrial fibrillation, pulmonary hypertension, elder; filling pressure) scores intermediate to the positive DST group and the group with both a normal DST and slope. CONCLUSIONS: Twenty-two percent of patients with suspected HFpEF presented with a mPAP/CO slope>3 mm Hg/L per min despite a negative DST. These patients had HFpEF characteristics and a peak oxygen uptake as low as patients with a positive DST. Therefore, an elevated mPAP/CO slope might indicate HFpEF irrespective of the DST result.

Predictive value of C-X-C motif chemokine receptor 4-directed molecular imaging in patients with advanced adrenocortical carcinoma.

BACKGROUND: In patients affected with adrenocortical carcinoma (ACC), C-X-C motif chemokine receptor 4 (CXCR4) is highly expressed in sites of disease in an ex-vivo setting. We aimed to determine the predictive value of CXCR4-targeting [68Ga]Ga-PentixaFor PET/CT for outcome when compared to clinical parameters. METHODS: We identified 41 metastasized ACC patients imaged with [68Ga]Ga-PentixaFor PET/CT. Scans were assessed visually and on a quantitative level by manually segmenting the tumor burden (providing tumor volume [TV], peak/mean/maximum standardized uptake values [SUV] and tumor chemokine receptor binding on the cell surface [TRB], defined as SUVmean multiplied by tumor volume). Clinical parameters included sex, previous therapies, age, Weiss-Score, and Ki67 index. Following imaging, overall survival (OS) was recorded. RESULTS: After [68Ga]Ga-PentixaFor PET/CT, median OS was 9 months (range, 1-96 months). On univariable analysis, only higher TRB (per 10 ml, HR 1.004, 95%CI: 1.0001-1.007, P = 0.005) and presence of CXCR4-positive peritoneal metastases (PM) were associated with shorter OS (HR 2.03, 95%CI: 1.03-4.02, P = 0.04). Presence of CXCR4-positive liver metastases (LM) trended towards significance (HR 1.85, 0.9-4.1, P = 0.11), while all other parameters failed to predict survival. On multivariable analysis, only TRB was an independent predictor for OS (HR 1.0, 95%CI: 1.00-1.001, P = 0.02). On Kaplan-Meier analysis, TRB above median (13.3 months vs. below median, 6.4 months) and presence of CXCR4-positive PM (6.4 months, vs. no PM, 11.4 months) were associated with shorter survival (P < 0.05, respectively). Presence of LM, however, was also linked to less favorable outcome (8.5 months vs. no LM, 18.1 months), without reaching significance (P = 0.07). CONCLUSIONS: In advanced ACC, elevated tumor chemokine receptor binding on the tumor cell surface detected through [68Ga]Ga-PentixaFor PET/CT is an independent predictor for OS, while other imaging and clinical parameters failed to provide relevant prognostic information.

Navigating new horizons: Prospects of NET-targeted radiopharmaceuticals in precision medicine.

In the evolving landscape of precision medicine, NET-targeted radiopharmaceuticals are emerging as pivotal tools for the diagnosis and treatment of a range of conditions, from heart failure and neurodegenerative disorders to neuroendocrine cancers. This review evaluates the advancements offered by 18F-labeled PET tracers and 211At alpha-particle therapy, juxtaposed with current 123I-MIBG SPECT and 131I-MIBG therapies. The enhanced spatial resolution and capability for quantitative analysis render 18F-labeled PET tracers potential candidates for improved detection and management of diseases. Alpha-particle therapy with 211At may offer increased specificity and tumoricidal efficacy, pointing towards a shift in therapeutic protocols. While preliminary data is promising, these innovative approaches require thorough validation against current modalities. Ongoing clinical trials are pivotal to confirm the expected clinical benefits and to address safety concerns. This review underscores the need for rigorous research to verify the clinical utility of NET-targeted radiopharmaceuticals, which may redefine precision medicine paradigms and significantly impact patient care.

Serial cardiac biomarkers, pulmonary artery pressures and traditional parameters of fluid status in relation to prognosis in patients with chronic heart failure: Design and rationale of the BioMEMS study.

AIMS: Heart failure (HF), a global pandemic affecting millions of individuals, calls for adequate predictive guidance for improved therapy. Congestion, a key factor in HF-related hospitalizations, further underscores the need for timely interventions. Proactive monitoring of intracardiac pressures, guided by pulmonary artery (PA) pressure, offers opportunities for efficient early-stage intervention, since haemodynamic congestion precedes clinical symptoms. METHODS: The BioMEMS study, a substudy of the MONITOR-HF trial, proposes a multifaceted approach integrating blood biobank data with traditional and novel HF parameters. Two additional blood samples from 340 active participants in the MONITOR-HF trial were collected at baseline, 3-, 6-, and 12-month visits and stored for the BioMEMS biobank. The main aims are to identify the relationship between temporal biomarker patterns and PA pressures derived from the CardioMEMS-HF system, and to identify the biomarker profile(s) associated with the risk of HF events and cardiovascular death. CONCLUSION: Since the prognostic value of single baseline measurements of biomarkers like N-terminal pro-B-type natriuretic peptide is limited, with the BioMEMS study we advocate a dynamic, serial approach to better capture HF progression. We will substantiate this by relating repeated biomarker measurements to PA pressures. This design rationale presents a comprehensive review on cardiac biomarkers in HF, and aims to contribute valuable insights into personalized HF therapy and patient risk assessment, advancing our ability to address the evolving nature of HF effectively.

The cutting edge: Promising oncology radiotracers in clinical development.

Molecular imaging moves forward with the development of new imaging agents, and among these are new radiotracers for nuclear medicine applications, particularly positron emission tomography (PET). A number of new targets are becoming accessible for use in oncologic applications. In this review, major new radiotracers in clinical development are discussed. Prominent among these is the family of fibroblast-activation protein-targeted agents that interact with the tumor microenvironment and may show superiority to 2-deoxy-2-[18F]fluoro-d-glucose in a subset of different tumor histologies. Additionally, carbonic anhydrase IX (CAIX) inhibitors are directed at clear cell renal cell carcinoma, which has long lacked an effective PET imaging agent. Those CAIX agents may also have utility in hypoxic tumors. Pentixafor, which binds to a transmembrane receptor, may similarly allow for visualization by PET of low-grade lymphomas, as well as being a second agent for multiple myeloma that opens theranostic possibilities. There are new adrenergic agents aimed at providing a PET-visible replacement to the single-photon-emitting radiotracer meta-[123I]iodobenzylguanidine (MIBG). Finally, in response to a major development in oncologic chemotherapy, there are new radiotracers targeted at assessing the suitability or use of immunotherapeutic agents. All of these and the existing evidence for their utility are discussed.

Dutch cardio-oncology cohort: Incident cardiovascular disease predisposes to a higher cancer mortality rate.

BACKGROUND: Cardiovascular disease (CVD) and cancer are the two leading causes of death worldwide. Given their high prevalence, it is important to understand the disease burden of cancer mortality in CVD patients. OBJECTIVE: We aimed to evaluate whether patients with incident CVD have a higher risk of malignancy-related mortality, compared to the general population without CVD. METHODS: We performed a national population-based cohort study selecting patients with incident CVD in the Netherlands between 01 April 2000 and 31 December 2005. A reference cohort was selected from the Dutch population using age, sex and ethnicity. Mortality follow-up data were evaluated after data linkage of national registries from Statistics Netherlands until 31 December 2020. RESULTS: A total of 2,240,879 individuals were selected with a mean follow-up of 12 years (range 0.4-21.0), of which 738,666 patients with incident CVD with a mean age of 71 ± 15 years. Malignancy mortality per 1000 person years was 84 for the reference group and 118 for patients with CVD, with the highest rate of 258 in patients with heart failure. Patients with CVD had a higher malignancy mortality risk, compared to the reference group: HR 1.35 (95%CI 1.33-1.36). Highest risks were observed in patients with venous diseases (HR 2.27, 95%CI 2.17-2.36) and peripheral artery disease (HR 1.87, 95%CI 1.84-2.01). CONCLUSION: Results show that CVD predisposes to a higher cancer mortality rate. Of all CVD subtypes, HF patients have the highest cancer mortality rate and the hazards were highest in patients with venous diseases and peripheral artery disease.

Artificial intelligence-assisted automated heart failure detection and classification from electronic health records.

AIMS: Electronic health records (EHR) linked to Digital Imaging and Communications in Medicine (DICOM), biological specimens, and deep learning (DL) algorithms could potentially improve patient care through automated case detection and surveillance. We hypothesized that by applying keyword searches to routinely stored EHR, in conjunction with AI-powered automated reading of DICOM echocardiography images and analysing biomarkers from routinely stored plasma samples, we were able to identify heart failure (HF) patients. METHODS AND RESULTS: We used EHR data between 1993 and 2021 from Tayside and Fife (~20% of the Scottish population). We implemented a keyword search strategy complemented by filtering based on International Classification of Diseases (ICD) codes and prescription data to EHR data set. We then applied DL for the automated interpretation of echocardiographic DICOM images. These methods were then integrated with the analysis of routinely stored plasma samples to identify and categorize patients into HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), and controls without HF. The final diagnosis was verified through a manual review of medical records, measured natriuretic peptides in stored blood samples, and by comparing clinical outcomes among groups. In our study, we selected the patient cohort through an algorithmic workflow. This process started with 60 850 EHR data and resulted in a final cohort of 578 patients, divided into 186 controls, 236 with HFpEF, and 156 with HFrEF, after excluding individuals with mismatched data or significant valvular heart disease. The analysis of baseline characteristics revealed that compared with controls, patients with HFrEF and HFpEF were generally older, had higher BMI, and showed a greater prevalence of co-morbidities such as diabetes, COPD, and CKD. Echocardiographic analysis, enhanced by DL, provided high coverage, and detailed insights into cardiac function, showing significant differences in parameters such as left ventricular diameter, ejection fraction, and myocardial strain among the groups. Clinical outcomes highlighted a higher risk of hospitalization and mortality for HF patients compared with controls, with particularly elevated risk ratios for both HFrEF and HFpEF groups. The concordance between the algorithmic selection of patients and manual validation demonstrated high accuracy, supporting the effectiveness of our approach in identifying and classifying HF subtypes, which could significantly impact future HF diagnosis and management strategies. CONCLUSIONS: Our study highlights the feasibility of combining keyword searches in EHR, DL automated echocardiographic interpretation, and biobank resources to identify HF subtypes.

Prostate-specific Membrane Antigen: Diagnostics.

Since its clinical introduction in May 2011, prostate-specific membrane antigen (PSMA)-PET/computed tomography has quickly gained worldwide recognition as a significant breakthrough in prostate cancer diagnostics. In the meantime, several new PSMA radioligands for PET imaging have been introduced into routine clinical practice. This article aims to introduce the most commonly used tracers and their key areas of application.

Dapagliflozin and quality of life measured using the EuroQol 5-dimension questionnaire in patients with heart failure with reduced and mildly reduced/preserved ejection fraction.

AIMS: Although much is known about the usefulness of heart failure (HF)-specific instruments for assessing patient well-being, less is known about the value of generic instruments for the measurement of health-related quality of life (HRQL) in HF. The aim of this study was to assess the relationship between the EuroQol 5-dimension 5-level (EQ-5D-5L) visual analogue scale (VAS) and index scores, clinical characteristics, and outcomes in patients with HF and the effect of dapagliflozin on these scores. METHODS AND RESULTS: We performed a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which investigated the effectiveness and safety of dapagliflozin in patients with HF and reduced ejection fraction (HFrEF) and mildly reduced/preserved ejection fraction (HFmrEF/HFpEF), respectively. Patients reporting higher (better) EQ-5D-5L VAS and index scores had a lower prevalence of comorbidities, including atrial fibrillation and hypertension, than patients with a worse score. They were also more likely to have better investigator-reported (New York Heart Association class) and patient-self-reported (Kansas City Cardiomyopathy Questionnaire) health status and lower median N-terminal pro-B-type natriuretic peptide levels. Compared to patients with the lowest scores (Q1), those with higher EQ-5D-5L VAS scores had better outcomes: the hazard ratio for the composite of cardiovascular death or worsening HF was 0.81 (95% confidence interval 0.72-0.91) in Q2, 0.74 (0.65-0.84) in Q3, and 0.62 (0.54-0.72) in Q4. The risk of each component of the composite outcome, and all-cause death, was also lower in patients with better scores. Similar findings were observed for the index score. Treatment with dapagliflozin improved both EQ-5D-5L VAS and index scores across the range of ejection fraction. CONCLUSIONS: Both higher (better) EQ-5D-5L VAS and index scores were associated with better outcomes. Dapagliflozin treatment improved EQ-5D-5L VAS and index scores, irrespective of ejection fraction.

Effect of dapagliflozin in patients with diabetes and heart failure with mildly reduced or preserved ejection fraction according to background glucose-lowering therapy: A pre-specified analysis of the DELIVER trial.

AIMS: Type 2 diabetes (T2D) and heart failure (HF) frequently coexist, but whether clinical outcomes and treatment effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vary in relation to background glucose-lowering therapy (GLT) in this population is uncertain. METHODS AND RESULTS: DELIVER randomized patients with HF and left ventricular ejection fraction (LVEF) >40% to dapagliflozin or placebo. The primary outcome was a composite of worsening HF (HF hospitalization or urgent HF visit) or cardiovascular death. In this pre-specified analysis of participants with T2D, treatment effects were assessed by number and class of background GLT(s). Of 3150 participants with T2D at baseline, 22.9% were on no GLT, 36.5% were treated with 1 GLT, and 40.6% with ≥2 GLTs. During follow-up (median: 2.3 years), treatment benefits of dapagliflozin (vs. placebo) on the primary outcome were consistent irrespective of the number of background GLTs (0 GLTs: hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.50-1.00; 1 GLT: HR 1.04, 95% CI 0.80-1.34; ≥2 GLTs: HR 0.71, 95% CI 0.56-0.90; pinteraction = 0.59). Similar findings were observed among participants with (HR 0.73, 95% CI 0.59-0.92) and without background metformin use (HR 0.89, 95% CI 0.72-1.11; pinteraction = 0.22) and in participants with (HR 0.89, 95% CI 0.69-1.16) and without background insulin use (HR 0.78, 95% CI 0.65-0.95; pinteraction = 0.45). Dapagliflozin was well-tolerated irrespective of the number of background GLTs. CONCLUSIONS: Dapagliflozin safely and consistently improved clinical outcomes among individuals with T2D and HF with LVEF >40% irrespective of the number and class of background GLTs, and the benefits were not influenced by concomitant metformin or insulin use. These data bolster contemporary guidelines supporting first-line SGLT2i among individuals with T2D and HF, irrespective of background GLT.

[Clinical significance of neuroendocrine tumors : Incidence, symptoms, diagnosis, stage, and prognostic factors and their influence on disease management]. / Klinische Bedeutung von neuroendokrinen Tumoren : Häufigkeit, Symptome, Diagnose und Stadien und prognostische Faktoren und deren Einfluss auf das Krankheitsmanagement.

BACKGROUND: Neuroendocrine neoplasms (NEN) are heterogenous with an increasing incidence in recent years. OBJECTIVES: Overview on incidence, symptoms, diagnostics, grading, imaging and prognostic determinants, including factors having an impact on therapeutic management. METHODS: Review on current literature, including original articles, reviews, guidelines and expert opinions. RESULTS: NEN are mainly located in the gastrointestinal tract and their incidence has increased in recent years, mainly due to improved diagnostics, e.g., cross-sectional imaging. Clinical characteristics include hormone excess syndromes (carcinoid syndrome). Laboratory markers such as chromogranin A are commonly used as part of routine diagnostics, followed by endoscopic and endosonographic procedures, which also allow biopsies to be obtained. Tumor spread can be determined by contrast-enhanced computed tomography/magnetic resonance imaging (CT/MRI) or somatostatin receptor (SSRT)-PET/CT (positron emission tomography). Prognostic factors include Ki67 index, type, and grading. Resection with curative intent is the therapy of choice. In a metastasized setting, SSRT-directed treatment approaches are favored, while in dedifferentiated NEN, conventional chemotherapy is needed. CONCLUSION: A broad diagnostic armamentarium can be offered to NEN patients and the improved diagnostic procedures have most likely caused a raising incidence in recent years. Among others, prognostic factors are Ki67 and NEN subtypes; these clinical determinants also have an impact on patient management.

Long-term reliability of the phospholamban (PLN) p.(Arg14del) risk model in predicting major ventricular arrhythmia: a landmark study.

AIMS: Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up. METHODS AND RESULTS: We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6-3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79-0.87) and calibration slope of 0.97. CONCLUSION: The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)-positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up.

Dapagliflozin and Timing of Prior Heart Failure Hospitalization: A Patient-Level Meta-Analysis of DAPA-HF and DELIVER.

BACKGROUND: Patients recently hospitalized for heart failure (HF) are at a higher risk of adverse clinical outcomes, but they may experience a greater absolute and relative benefit from effective therapies than individuals who are considered more "stable." OBJECTIVES: The authors examined the effects of dapagliflozin according to the timing of prior HF hospitalization in a patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure). METHODS: A total of 11,007 patients were randomized in DAPA-HF and DELIVER. The primary outcome was the composite of worsening HF or cardiovascular death. RESULTS: In total, 12.4% were hospitalized for HF within 3 months of randomization, 14.2% between 3 and 12 months, and 16.8% more than 1 year before randomization, whereas 56.5% had not been hospitalized. The risk of the primary endpoint was inversely associated with time from prior HF hospitalization, and patients with a recent HF hospitalization had the highest risk. Compared with placebo, dapagliflozin reduced the risk of the primary outcome across HF hospitalization category (0-3 months, HR: 0.66 [95% CI: 0.55-0.81]; 3-12 months, HR: 0.73 [95% CI: 0.59-0.90]; >1 year, HR: 0.91 [95% CI: 0.74-1.12]; and no prior hospitalization, HR: 0.83 [95% CI: 0.73-0.94]; Pinteraction = 0.09). The number of patients needed to treat with dapagliflozin to prevent 1 event over the median follow-up of 22 months was 13, 20, 23, and 28, respectively. The beneficial effect was consistent across the range of LVEF regardless of HF hospitalization category. CONCLUSIONS: The relative benefits of dapagliflozin were consistent across the range of LVEF regardless of the timing of the most recent HF hospitalization with a greater absolute benefit in patients with recent hospitalization.