Tags:
Radiology,
MRI,
Cardiovascular disease
Publications
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Wimalanathan, Thakshani; Sulkowska, Joanna; Melles, Woldegabriel A; Paus, Michael Fredrik; Skranes, Julia Brox & Berge, Trygve
[Show all 11 contributors for this article]
(2026).
Myocardial fibrosis is associated with worse left ventricular strain and synchrony assessed by novel CMR imaging in the general population: data from the Akershus Cardiac examination 1950 study.
The International Journal of Cardiovascular Imaging.
ISSN 1569-5794.
doi:
10.1007/s10554-026-03746-1.
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Omland, Torbjørn; Heck, Siri Lagethon; Holte, Espen; Gynnild, Mari Nordbø; Gulati, Geeta & Wethal, Torgeir
(2026).
Response by Omland et al to Letter Regarding Article, “Sacubitril/Valsartan and Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy: The PRADA II Randomized Clinical Trial”.
Circulation.
ISSN 0009-7322.
153(22).
doi:
10.1161/circulationaha.126.079810.
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Paus, Michael Fredrik; Lyngbakken, Magnus Nakrem; Tveit, Arnljot; Steine, Kjetil; Berge, Trygve & Skranes, Julia Brox
[Show all 14 contributors for this article]
(2025).
Determinants of Cardiac Myosin Binding Protein C in the General Population.
Clinical Chemistry.
ISSN 0009-9147.
71(4),
p. 484–496.
doi:
10.1093/clinchem/hvaf013.
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Background: Cardiac myosin binding protein C (cMyC) is a novel, cardiac-specific biomarker with an early release profile after acute ischemic myocardial injury. Whether cMyC reflects chronic myocardial injury and left ventricular remodelling in the general population is unknown. The aims of the study were to test the hypotheses that cMyC concentrations are associated with cardiovascular risk factors, biomarkers of chronic myocardial injury, and imaging biomarkers of cardiac anatomy, function, and fibrosis.
Methods: Circulating cMyC and cardiac troponin I and T concentrations were measured in 3672 individuals from the general population, born in 1950, who underwent echocardiography. One-hundred-ninety-nine participants with measured cMyC completed a cardiovascular magnetic resonance (CMR) examination for assessment of myocardial fibrosis.
Results: Circulating cMyC was measurable in 99.6% of study participants and in 99.0% of CMR substudy participants. cMyC was positively associated with left ventricular mass and left atrial volume and inversely associated with renal function and indices of left ventricular systolic and diastolic function. In participants with available late gadolinium enhancement images for the assessment of focal fibrosis (n = 197), cMyC was positively associated with indices of focal myocardial fibrosis.
Conclusions: In the general population, circulating cMyC concentrations are associated with cardiovascular risk factors, reflect left ventricular remodelling, including focal myocardial fibrosis, and systolic and diastolic dysfunction independently of traditional risk factors.
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Gynnild, Mari Nordbø; Vinje-Jakobsen, Victoria; Holtrop, Joris; Hageman, Steven H.J.; Holte, Espen & Gulati, Geeta
[Show all 14 contributors for this article]
(2025).
Prognostic Performance of a Modified HFA-ICOS Tool for Prediction of Cardiovascular Complications in Cancer Patients.
JACC: Advances.
4(12).
doi:
10.1016/j.jacadv.2025.102344.
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Background
The 2022 European Society of Cardiology Cardio-oncology Guidelines recommend the Heart Failure Association and International Cardio-Oncology Society risk stratification tool to predict cardiovascular disease (CVD) risk in cancer patients. Developed from expert consensus rather than mathematical derivation, its quantitative prognostic value in unselected cancer populations remains uncertain.
Objectives
The objective of the study was to assess the prognostic utility of a modified Heart Failure Association and International Cardio-Oncology Society tool, excluding biomarkers and imaging, in predicting CVD complications in cancer patients, thereby providing a quantitative correlate to an expert consensus-based method.
Methods
We included 2,290 cancer patients from the third follow-up of the Trøndelag Health study, diagnosed within 4 years of participation, and followed through 2023. Cancer therapy details were obtained from the Norwegian Cancer Registry. The primary outcome was a composite of myocardial infarction, heart failure hospitalization, stroke, or CVD mortality, identified via national registries.
Results
The mean age was 65.8 years; 48% were female. The most common cancers were gastrointestinal (23%), prostate (19%), and breast (12%). The median follow-up was 6.9 years. The modified tool classified 28% as low-, 35% moderate-, 34% high-, and 3% very high-risk. CVD incidence rose across categories: 7%, 21%, 29%, and 37% (P < 0.001). The C-statistic was 0.696 (95% CI: 0.674-0.718), and 0.746 (95% CI: 0.676-0.812) among anthracycline-treated patients. Within the low-to-moderate group, event rates ranged from 6% to 8% (0-1 points) to 24% to 27% (3-4 points).
Conclusions
The tool stratifies CVD risk in cancer patients and may guide tailored follow-up and cardioprotection. Heterogeneity within moderate-risk patients highlights the need for refinement to improve individualized assessment.
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Chadwick, Jessica; Berry, Colin; Carpenter, Meredith A.; Gulati, Geeta; Heck, Siri Lagethon & Hinterberg, Michael A.
[Show all 18 contributors for this article]
(2025).
Utilization of Proteomic Measures for Early Detection of Drug Benefits and Adverse Effects.
Journal of clinical pharmacology.
ISSN 0091-2700.
65(11),
p. 1460–1473.
doi:
10.1002/jcph.70077.
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Recognition of benefits and adverse effects of therapies in earlier clinical trial phases could improve the safety, efficiency, and cost of clinical trials. Using four clinical trials representing a diverse set of diseases and drug classes (EXSCEL: exenatide/GLP‐1 RA, SUGAR‐DM‐HF: empagliflozin/SGLT2i, PRADA: epirubicin/anthracycline, and AMPLE: abatacept/immunomodulator and adalimumab/TNF inhibitor), we hypothesized that previously validated proteomic measures for cardiometabolic outcomes could enable the detection of beneficial and adverse drug effects in fewer participants over a shorter follow‐up period. Changes in SomaSignal TM proteomic tests over time in response to treatment were assessed in the EXSCEL (baseline vs 1 year; once‐weekly exenatide (EQW) (n) = 1812 vs control (n) = 1787), SUGAR‐DM‐HF (baseline vs 12 weeks and 36 weeks; empagliflozin (n) = 45 vs control (n) = 52), AMPLE (baseline vs 85 days and 1 year; abatacept (n) = 210, adalimumab (n) = 222), and PRADA (baseline vs 7–10 days and 3 months, n = 120) trial. Improvement of cardiovascular risk and cardiometabolic traits with EQW was detectable within 1 year ( P = .002) in sample sizes significantly smaller than the original study. Cardio‐ and kidney‐protective ( P = .06, P = .037) effects of empagliflozin were detectable within 36 weeks in a small sample size (n ∼ 50). Abatacept and adalimumab treatment demonstrated significant improvements in cardiovascular risk ( P ≤ .001, P ≤ .001) and cardiorespiratory fitness ( P ≤ .001, P ≤ .001) within 85 days. In contrast, anthracycline treatment led to significant increases in heart failure mortality risk ( P ≤ 0.001) and cardiovascular risk ( P = .004) after the first cycle of chemotherapy treatment. These findings provide preliminary evidence that proteomics may provide a powerful tool for optimizing drug pipelines by predicting the effects of novel therapeutics in smaller, shorter trials.
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Omland, Torbjørn; Heck, Siri Lagethon; Holte, Espen; Mecinaj, Albulena; Gynnild, Mari Nordbø & Fagerland, Morten
[Show all 13 contributors for this article]
(2025).
Sacubitril/Valsartan and Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy: The PRADA II Randomized Clinical Trial.
Circulation.
ISSN 0009-7322.
152(16),
p. 1136–1145.
doi:
10.1161/circulationaha.125.076616.
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Background: Anthracycline- and trastuzumab-associated cardiotoxicity may lead to cardiac dysfunction and dose reduction or halt in potentially life-saving adjuvant cancer therapy. Whether angiotensin receptor neprilysin inhibitors can prevent cancer therapy-related cardiac dysfunction and injury remains to be established. Methods: PRADA II was a randomized, parallel-group, placebo-controlled, double-blind multicenter trial conducted at 4 academic medical centers in Norway that evaluated the cardioprotective effect of sacubitril-valsartan vs. placebo administered concomitantly with anthracycline-containing breast cancer therapy and continued for 18 months. The target dose was 97/103 mg b.i.d. The primary outcome was change in left ventricular ejection fraction by cardiovascular magnetic resonance from prior to initiation of chemotherapy to 18 months after. Secondary outcomes included change in echocardiographic global longitudinal strain, circulating cardiac troponins, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Results: In total, 138 women (mean (±SD) age: 54.0 ± 9.4 years) were randomized. The overall decline in left ventricular ejection fraction from baseline to 18 months was 2.2 percentage points (95% confidence interval [CI], 1.1 to 3.3) in the placebo group and 1.1 percentage points (95% CI, -0.01 to 2.2) in the sacubitril-valsartan group. The between-group difference was 1.1 percentage points (95% CI, -0.4 to 2.7; P=0.16). Left ventricular global longitudinal strain was normal and remained stable in the sacubitril-valsartan group throughout the study (change from baseline to 18 months -0.32 [95% CI, -0.80 to 0.15]). In contrast, there was a progressive decline in the placebo group (change from baseline to 18 months 0.53 [95% CI, 0.05 to 1.00]). The between-group difference was -0.85 (95% CI, -1.52 to -0.18). The mean increases in NT-proBNP and cardiac troponin I concentrations from baseline to 18 months were greater in the placebo than in the sacubitril-valsartan group (log difference 0.303 (95% CI 0.0547 to 0.552) for NT-proBNP and 0.534 (95% CI 0.114 to 0.954) for cardiac troponin I). Conclusions: Anthracycline-based treatment for early breast cancer is associated with a reduction in left ventricular ejection fraction that was not significantly attenuated by sacubitril-valsartan.
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Wimalanathan, Thakshani; Paus, Michael Fredrik; Skranes, Julia Brox; Berge, Trygve; Tveit, Arnljot & Røsjø, Helge Rørvik
[Show all 9 contributors for this article]
(2024).
Associations between Growth Differentiation Factor 15, Cardiac Troponin T, and N-terminal pro-B-type Natriuretic Peptide, and Future Myocardial Fibrosis Assessed by Cardiac Magnetic Resonance Imaging: Data from the Akershus Cardiac Examination 1950 Study.
The Journal of Applied Laboratory Medicine (JALM).
ISSN 2576-9456.
10(2),
p. 392–405.
doi:
10.1093/jalm/jfae145.
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Background Myocardial fibrosis is associated with a poor outcome for patients with cardiovascular disease (CVD). Growth differentiation factor 15 (GDF-15) concentrations predict the risk of death in patients with CVD, but the underlying pathophysiological mechanisms are poorly understood. We aimed to assess the associations between biomarkers of cellular stress and inflammation (GDF-15), cardiac injury (cardiac troponin T [cTnT]), and stretch (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), and subsequent focal and diffuse myocardial fibrosis assessed by cardiac magnetic resonance (CMR) imaging. Methods We measured GDF-15, cTnT, and NT-proBNP in 200 study participants without known coronary artery disease or renal dysfunction from the population-based Akershus Cardiac Examination 1950 Study at baseline in 2012 to 2015. Focal myocardial scars and diffuse fibrosis were assessed by late gadolinium enhancement imaging and septal extracellular volume fraction (ECV) by CMR 4 to 7 years later. The relationships between cardiac biomarkers and CMR parameters were assessed by logistic regression analysis adjusted for common cardiovascular risk factors. Results The median age was 63.9 (interquartile range 63.4–64.5) years and 49% were women. GDF-15 (adjusted odds ratio [aOR] 4.40, 95% CI 1.09–17.72) and cTnT (aOR 1.59, 95% CI 1.01–2.50) were associated with nonischemic scars in the fully adjusted model. cTnT (aOR 2.45, 95% CI 1.41–4.25) and NT-proBNP (aOR 3.12, 95% CI 1.55–6.28) were associated with ischemic scars. None of the biomarkers were significantly associated with elevated ECV. Conclusions In a general population cohort, GDF-15, an emerging biomarker of cellular stress and inflammation, associates with nonischemic scars. Biomarkers of myocardial injury and stretch associate with ischemic scars, while no biomarker was associated with diffuse fibrosis as assessed by CMR.
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Sulkowska, Joanna; Melles, Woldegabriel A; Skranes, Julia Brox; Berge, Trygve; Tveit, Arnljot & Røsjø, Helge Rørvik
[Show all 9 contributors for this article]
(2024).
Cardiac troponin T associates with left ventricular function and synchrony assessed by CMR in the general population: results from the Akershus Cardiac Examination 1950 Study.
European Heart Journal – Imaging Methods and Practice (EHJ-IMP).
2(3).
doi:
10.1093/ehjimp/qyae078.
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Background and aim Cardiac troponin T (cTnT) is a blood biomarker of myocardial injury that is associated with future adverse cardiovascular events in the general population. Left ventricular (LV) global longitudinal strain (GLS) and mechanical dispersion (MD) are metrics of systolic function and synchrony that can be obtained from cardiac imaging. Studies suggest an association between cTnT and echocardiographically assessed GLS and MD, but it is unknown whether cTnT relates to these metrics when assessed by cardiac magnetic resonance (CMR). We hypothesized that cTnT associates with GLS and with MD assessed by CMR feature tracking (CMR-FT) in the general population. Methods and results cTnT and CMR-FT measurements were performed in 186 community dwellers from the Akershus Cardiac Examination 1950 Study. The participants’ age ranged from 68 to 70 years. Median cTnT concentration was 7.0 ng/L (interquartile interval 5.0–12.6 ng/L), median absolute value of GLS was 17.3% (interquartile interval 15.7–18.8%), and median MD was 80.7 milliseconds (interquartile interval 61.8–105.0 milliseconds). In multivariable linear regression models adjusted for common clinical risk factors of cardiovascular disease, with GLS and MD as outcome and cTnT as the predictor variable of interest, log10 transformed cTnT was significantly associated with both absolute GLS [β-coefficient −1.65, confidence interval (−2.84, −0.46)] and MD [β-coefficient 28.56, confidence interval (12.14, 44.92)]. Conclusion In older adults from the general population, higher cTnT concentrations are associated with worse systolic function and synchrony assessed by CMR-FT LV GLS and MD, adding information about myocardial function to traditional risk factors.
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Mecinaj, Albulena; Gulati, Geeta; Ree, Anne Hansen; Gravdehaug, Berit; Røsjø, Helge Rørvik & Steine, Kjetil
[Show all 10 contributors for this article]
(2024).
Impact of the ESC Cardio-Oncology Guidelines Biomarker Criteria on Incidence of Cancer Therapy–Related Cardiac Dysfunction.
JACC: CardioOncology.
6(1),
p. 83–95.
doi:
10.1016/j.jaccao.2023.10.008.
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Background The impact of recent consensus definitions of cancer therapy–related cardiac dysfunction (CTRCD) from the European Society of Cardiology cardio-oncology guidelines on the reported incidence of CTRCD has not yet been assessed. Objectives The aim of this study was to assess the: 1) cumulative incidence; 2) point prevalence during and after adjuvant therapy; and 3) prognostic value of CTRCD as defined by different asymptomatic CTRCD guideline criteria. Methods The cumulative incidence and point prevalence of CTRCD were retrospectively assessed in 118 patients participating in the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial. Asymptomatic CTRCD was assessed using alternative cardiac troponin (cTn) 99th percentile upper reference limits (URLs) to define cTnT and cTnI elevation. Results The cumulative incidence of moderate or severe CTRCD was low (1.7%), whereas the cumulative incidence of mild asymptomatic CTRCD was higher and differed markedly according to the biomarker criteria applied, ranging from 49.2% of patients when cTnT greater than the sex-specific 99th percentile URL was used to define cTn elevation to 9.3% when sex-neutral cTnI was used. The point prevalence of CTRCD was highest at the end of anthracycline therapy (47.8%) and was driven primarily by asymptomatic cTn elevation. CTRCD during adjuvant therapy was not prognostic for CTRCD at extended follow-up of 24 months (Q1-Q3: 21-29 months) after randomization. Conclusions Mild asymptomatic CTRCD during adjuvant breast cancer therapy was frequent and driven mainly by cTn elevation and was not prognostic of subsequent CTRCD. The incidence of mild, asymptomatic CTRCD differed markedly depending on the cTn assay and whether sex-neutral or sex-dependent URLs were applied. (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy [PRADA]; NCT01434134)
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Øvrebotten, Tarjei; Mecinaj, Albulena; Stavem, Knut; Ghanima, Waleed; Brønstad, Eivind & Durheim, Michael Thomas
[Show all 14 contributors for this article]
(2024).
Trajectory of cardiac troponin T following moderate-to-severe COVID-19 and the association with cardiac abnormalities.
BMC Cardiovascular Disorders.
24(1).
doi:
10.1186/s12872-024-03854-7.
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Background COVID-19 has been associated with cardiac troponin T (cTnT) elevations and changes in cardiac structure and function, but the link between cardiac dysfunction and high-sensitive cardiac troponin T (hs-cTnT) in the acute and convalescent phase is unclear. Objective To assess whether hs-cTnT concentrations are associated with cardiac dysfunction and structural abnormalities after hospitalization for COVID-19, and to evaluate the performance of hs-cTnT to rule out cardiac pathology. Methods Patients hospitalized with COVID-19 had hs-cTnT measured during the index hospitalization and after 3-and 12 months, when they also underwent an echocardiographic study. A subset also underwent cardiovascular magnetic resonance imaging (CMR) after 6 months. Cardiac abnormalities were defined as left ventricular hypertrophy or dysfunction, right ventricular dysfunction, or CMR late gadolinium. Results We included 189 patients with hs-cTnT concentrations measured during hospitalization for COVID-19, and after 3-and 12 months: Geometric mean (95%CI) 13 (11–15) ng/L, 7 (6–8) ng/L and 7 (6–8) ng/L, respectively. Cardiac abnormalities after 3 months were present in 45 (30%) and 3 (8%) of patients with hs-cTnT ≥ and < 5 ng/L at 3 months, respectively (negative predictive value 92.3% [95%CI 88.5–96.1%]). The performance was similar in patients with and without dyspnea. Hs-cTnT decreased from hospitalization to 3 months (more pronounced in intensive care unit-treated patients) and remained unchanged from 3 to 12 months, regardless of the presence of cardiac abnormalities. Conclusion Higher hs-cTnT concentrations in the convalescent phase of COVID-19 are associated with the presence of cardiac pathology and low concentrations (< 5 ng/L) may support in ruling out cardiac pathology following the infection.
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Øvrebotten, Tarjei; Heck, Siri Lagethon; Skjørten, Ingunn; Einvik, Gunnar; Stavem, Knut & Ingul, Charlotte Ingeborg Björk
[Show all 8 contributors for this article]
(2023).
Minor Myocardial Scars in Association with Cardiopulmonary Function after COVID-19.
Cardiology.
ISSN 0008-6312.
148(4),
p. 300–306.
doi:
10.1159/000530942.
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Background: Myocardial scars detected by cardiovascular magnetic resonance (CMR) imaging after COVID-19 have caused concerns regarding potential long-term cardiovascular consequences. Objective: The objective of this study was to investigate cardiopulmonary functioning in patients with versus without COVID-19-related myocardial scars. Methods: In this prospective cohort study, CMR was performed approximately 6 months after moderate-to-severe COVID-19. Before (∼3 months post-COVID-19) and after (∼12 months post-COVID-19) the CMR, patients underwent extensive cardiopulmonary testing with cardiopulmonary exercise tests, 24-h ECG, and echocardiography. We excluded participants with overt heart failure. Results: Post-COVID-19 CMR was available in 49 patients with cardiopulmonary tests at 3 and 12 months after the index hospitalization. Nine (18%) patients had small late gadolinium enhancement-detected myocardial scars. Patients with myocardial scars were older (63.2 ± 13.2 vs. 56.2 ± 13.2 years) and more frequently men (89% vs. 55%) compared to those without scars. Cardiorespiratory fitness was similar in patients with and without scars, i.e., peak oxygen uptake: 82.1 ± 11.5% versus 76.3 ± 22.5% of predicted, respectively (p = 0.46). The prevalence of ventricular premature contractions and arrhythmias was low and not different by the presence of myocardial scar. Cardiac structure and function assessed by echocardiography were similar between the groups, except for a tendency of greater left ventricular mass in those with scars (75 ± 20 vs. 62 ± 14, p = 0.02 and p = 0.08 after adjusting for age and sex). There were no significant associations between myocardial scar and longitudinal changes in cardiopulmonary function from 3 to 12 months. Conclusion: Our findings imply that the presence of minor myocardial scars has limited clinical significance with respect to cardiopulmonary function after COVID-19.
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Omland, Torbjørn; Heck, Siri Lagethon & Gulati, Geeta
(2022).
The Role of Cardioprotection in Cancer Therapy Cardiotoxicity: JACC: CardioOncology State-of-the-Art Review.
JACC: CardioOncology.
4(1),
p. 19–37.
doi:
10.1016/j.jaccao.2022.01.101.
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Cardiotoxicity is a relatively frequent and potentially serious side effect of traditional and targeted cancer therapies. Both general measures and specific pharmacologic cardioprotective interventions as well as imaging- and biomarker-based surveillance strategies to identify patients at high risk have been tested in randomized controlled trials to prevent or attenuate cancer therapy–related cardiotoxic effects. Although meta-analyses including early trials suggest an overall beneficial effect, there is substantial heterogeneity in results. Recent randomized controlled trials of neurohormonal inhibitors in patients receiving anthracyclines and/or human epidermal growth factor receptor 2–targeted therapies have shown a lower rate of cancer therapy–related cardiac dysfunction than previously reported and a modest or no sustained effect of the interventions. Data on preventive cardioprotective strategies for novel cancer drugs are lacking. Larger, prospective multicenter randomized clinical trials testing traditional and novel interventions are required to more accurately define the benefit of different cardioprotective strategies and to refine risk prediction and identify patients who are likely to benefit.
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Myhre, Peder Langeland; Heck, Siri Lagethon; Skranes, Julia Brox; Prebensen, Christian Haugland; Jonassen, Christine M & Berge, Trygve
[Show all 15 contributors for this article]
(2021).
Cardiac pathology 6 months after hospitalization for COVID-19 and association with the acute disease severity.
American Heart Journal.
ISSN 0002-8703.
242,
p. 61–70.
doi:
10.1016/j.ahj.2021.08.001.
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Background Coronavirus disease 2019 (COVID-19) may cause myocardial injury and myocarditis, and reports of persistent cardiac pathology after COVID-19 have raised concerns of long-term cardiac consequences. We aimed to assess the presence of abnormal cardiovascular resonance imaging (CMR) findings in patients recovered from moderate-to-severe COVID-19, and its association with markers of disease severity in the acute phase. Methods Fifty-eight (49%) survivors from the prospective COVID MECH study, underwent CMR median 175 [IQR 105-217] days after COVID-19 hospitalization. Abnormal CMR was defined as left ventricular ejection fraction (LVEF) <50% or myocardial scar by late gadolinium enhancement. CMR indices were compared to healthy controls (n = 32), and to circulating biomarkers measured during the index hospitalization. Results Abnormal CMR was present in 12 (21%) patients, of whom 3 were classified with major pathology (scar and LVEF <50% or LVEF <40%). There was no difference in the need of mechanical ventilation, length of hospital stay, and vital signs between patients with vs without abnormal CMR after 6 months. Severe acute respiratory syndrome coronavirus 2 viremia and concentrations of inflammatory biomarkers during the index hospitalization were not associated with persistent CMR pathology. Cardiac troponin T and N-terminal pro-B-type natriuretic peptide concentrations on admission, were higher in patients with CMR pathology, but these associations were not significant after adjusting for demographics and established cardiovascular disease. Conclusions CMR pathology 6 months after moderate-to-severe COVID-19 was present in 21% of patients and did not correlate with severity of the disease. Cardiovascular biomarkers during COVID-19 were higher in patients with CMR pathology, but with no significant association after adjusting for confounders. Trial Registration COVID MECH Study ClinicalTrials.gov Identifier: NCT04314232
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Heck, Siri Lagethon; Mecinaj, Albulena; Ree, Anne Hansen; Hoffmann, Pavel; Schulz-Menger, Jeanette & Fagerland, Morten
[Show all 12 contributors for this article]
(2021).
Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): Extended follow-up of a 2×2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol.
Circulation.
ISSN 0009-7322.
143(25),
p. 2431–2440.
doi:
10.1161/CIRCULATIONAHA.121.054698.
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Background: Adjuvant breast cancer therapy containing anthracyclines with or without anti–human epidermal growth factor receptor–2 antibodies and radiotherapy is associated with cancer treatment–related cardiac dysfunction. In the PRADA trial (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy), concomitant treatment with the angiotensin receptor blocker candesartan attenuated the reduction in left ventricular ejection fraction (LVEF) in women receiving treatment for breast cancer, whereas the β-blocker metoprolol attenuated the increase in cardiac troponins. This study aimed to assess the long-term effects of candesartan and metoprolol or their combination to prevent a reduction in cardiac function and myocardial injury. Methods: In this 2×2 factorial, randomized, placebo-controlled, double-blind, single-center trial, patients with early breast cancer were assigned to concomitant treatment with candesartan cilexetil, metoprolol succinate, or matching placebos. Target doses were 32 and 100 mg, respectively. Study drugs were discontinued after adjuvant therapy. All 120 validly randomized patients were included in the intention-to-treat analysis. The primary outcome measure was change in LVEF assessed by cardiovascular magnetic resonance imaging from baseline to extended follow-up. Secondary outcome measures included changes in left ventricular volumes, echocardiographic peak global longitudinal strain, and circulating cardiac troponin concentrations. Results: A small decline in LVEF but no significant between-group differences were observed from baseline to extended follow-up, at a median of 23 months (interquartile range, 21 to 28 months) after randomization (candesartan, 1.7% [95% CI, 0.5 to 2.8]; no candesartan, 1.8% [95% CI, 0.6 to 3.0]; metoprolol, 1.6% [95% CI, 0.4 to 2.7]; no metoprolol, 1.9% [95% CI, 0.7 to 3.0]). Candesartan treatment during adjuvant therapy was associated with a significant reduction in left ventricular end-diastolic volume compared with the noncandesartan group (P=0.021) and attenuated decline in global longitudinal strain (P=0.046) at 2 years. No between-group differences in change in cardiac troponin I and T concentrations were observed. Conclusions: Anthracycline-containing adjuvant therapy for early breast cancer was associated with a decline in LVEF during extended follow-up. Candesartan during adjuvant therapy did not prevent reduction in LVEF at 2 years, but was associated with modest reduction in left ventricular end-diastolic volume and preserved global longitudinal strain. These results suggest that a broadly administered cardioprotective approach may not be required in most patients with early breast cancer without preexisting cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01434134.
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Mecinaj, Albulena; Gulati, Geeta; Heck, Siri Lagethon; Holte, Espen; Fagerland, Morten Wang & Larsen, Alf Inge
[Show all 10 contributors for this article]
(2021).
Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial.
Cardio-Oncology.
7.
doi:
10.1186/s40959-021-00115-w.
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Objective
To assess if sacubitril/valsartan given concomitantly with early breast cancer treatment regimens including anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction.
Methods
PRADA II is a randomized, placebo-controlled, double blind, multi-center, investigator-initiated clinical trial. Breast cancer patients from four university hospitals in Norway, scheduled to receive (neo-)adjuvant chemotherapy with epirubicin independently of additional trastuzumab/pertuzumab treatment, will be randomized 1:1 to sacubitril/valsartan or placebo. The target dose is 97/103 mg b.i.d. The patients will be examined with cardiovascular magnetic resonance (CMR), echocardiography, circulating cardiovascular biomarkers and functional testing at baseline, at end of anthracycline treatment and following 18 months after enrolment. The primary outcome measure of the PRADA II trial is the change in left ventricular ejection fraction (LVEF) by CMR from baseline to 18 months. Secondary outcomes include change in LV function by global longitudinal strain by CMR and echocardiography and change in circulating cardiac troponin concentrations.
Results
The study is ongoing. Results will be published when the study is completed.
Conclusion
PRADA II is the first randomized, placebo-controlled study of sacubitril/valsartan in a cardioprotective setting during (neo-)adjuvant breast cancer therapy. It may provide new insight in prevention of cardiotoxicity in patients receiving adjuvant or neo-adjuvant therapy containing anthracyclines. Furthermore, it may enable identification of patients at higher risk of developing cardiotoxicity and identification of those most likely to respond to cardioprotective therapy.
Trial registration
The trial is registered in the ClinicalTrials.gov registry (identifier NCT03760588). Registered 30 November 2018.
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Gulati, Geeta; Heck, Siri Lagethon; Røsjø, Helge; Ree, Anne Hansen; HOFFMANN, PAVEL & Hagve, Tor-Arne
[Show all 11 contributors for this article]
(2017).
Neurohormonal blockade and circulating cardiovascular biomarkers during anthracycline therapy in breast cancer patients: Results from the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) study.
Journal of the American Heart Association (JAHA).
6(11).
doi:
10.1161/JAHA.117.006513.
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Background Anthracyclines are associated with cardiotoxic effects. Cardiovascular biomarkers may reflect myocardial injury, dysfunction, inflammation, and fibrosis and may precede and predict the development of left ventricular impairment. The aim of this study was to assess: (1) longitudinal change in circulating cardiovascular biomarkers, (2) the effect of metoprolol succinate and candesartan cilexetil on the biomarker response, and (3) the associations between on‐treatment changes in biomarker concentrations and subsequent left ventricular dysfunction in patients with early breast cancer receiving anthracyclines. Methods and Results This report encompasses 121 women included in the 2×2 factorial, placebo‐controlled, double‐blind PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial with metoprolol and candesartan given concomitantly with anticancer therapy containing the anthracycline, epirubicin (total cumulative dose, 240–400 mg/m2). Cardiovascular magnetic resonance, echocardiography images, and circulating levels of biomarkers were obtained before and after anthracycline treatment. Cardiac troponins I and T, B‐type natriuretic peptide, N‐terminal pro‐B‐type natriuretic peptide, C‐reactive protein, and galectin‐3 increased during anthracycline therapy (all P<0.05). The troponin response was attenuated by metoprolol (P<0.05), but not candesartan. There was no association between change in biomarker concentrations and change in cardiac function during anthracycline therapy. Conclusions Treatment with contemporary anthracycline doses for early breast cancer is associated with increase in circulating cardiovascular biomarkers. This increase is, however, not associated with early decline in ventricular function. Beta‐blockade may attenuate early myocardial injury, but whether this attenuation translates into reduced risk of developing ventricular dysfunction in the long term remains unclear. Clinical Trial Registration URL: http://www.clinicaltrial.gov. Unique identifier: NCT01434134.
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Heck, Siri Lagethon; Gulati, Geeta; HOFFMANN, PAVEL; Knobelsdorff-Brenkenhoff, Florian von; Storås, Tryggve & Ree, Anne Hansen
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(2017).
Effect of candesartan and metoprolol on myocardial tissue composition during anthracycline treatment: The PRADA trial.
European Heart Journal-Cardiovascular Imaging.
ISSN 2047-2404.
19(5),
p. 544–552.
doi:
10.1093/ehjci/jex159.
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Aims:
Anthracycline treatment may cause myocyte loss and expansion of the myocardial extracellular volume (ECV) fraction by oedema and fibrosis. We tested the hypotheses that adjuvant treatment for early breast cancer with the anthracycline epirubicin is dose dependently associated with increased ECV fraction and total ECV, as well as reduced total myocardial cellular volume, and that these changes could be prevented by concomitant angiotensin or beta-adrenergic blockade.
Methods and results:
PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA) was a 2 × 2 factorial, placebo-controlled, double-blinded trial of candesartan and metoprolol. Sixty-nine women had valid ECV measurements. ECV fraction, total ECV, and total cellular volume were measured by cardiovascular magnetic resonance before and at the completion of anthracycline therapy. ECV fraction increased from 27.5 ± 2.7% to 28.6 ± 2.9% (P = 0.002). A cumulative doxorubicin equivalent dose of 268 mg/m2 was associated with greater increase in ECV fraction than doses <268 mg/m2 (mean change 3.4% [95% confidence interval (CI) 1.2, 5.5] vs. 0.7% [95% CI 0.0, 1.5], P = 0.006), as well as greater increase in total ECV (1.9 mL [95% CI 0.4, 3.5] vs. 0.1 mL [95% CI -0.6, 0.8], P = 0.04). In patients receiving candesartan, total cellular volume decreased (-3.5 mL [95% CI - 4.7, -2.2], P < 0.001) while in patients not receiving candesartan, it remained unchanged (P = 0.45; between group difference P = 0.003).
Conclusions:
Anthracycline therapy is associated with dose-dependent increase in ECV fraction and total ECV. Concomitant treatment with candesartan reduces left ventricular total cellular volume.
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Gulati, Geeta; Heck, Siri Lagethon; Ree, Anne Hansen; HOFFMANN, PAVEL; Schulz-Menger, Jeanette & Fagerland, Morten
[Show all 15 contributors for this article]
(2016).
Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 x 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol.
European Heart Journal.
ISSN 0195-668X.
37(21),
p. 1671–1680.
doi:
10.1093/eurheartj/ehw022.
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Vinje-Jakobsen, Victoria; Gynnild, Mari Nordbø; Mecinaj, Albulena; Wisløff, Torbjørn; Holte, Espen & Wethal, Torgeir
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(2026).
The effect of sacubitril/valsartan on functional disability and skeletal muscle injury during breast cancer therapy: insights from the PRADA II trial.
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Background: Anthracycline therapy induces dose-dependent cardiotoxicity and systemic adverse effects, including functional disability. While sacubitril/valsartan attenuates early subclinical myocardial injury during breast cancer therapy, its impact on functional capacity and skeletal muscle injury remains unknown.
Purpose: To evaluate whether sacubitril/valsartan attenuates anthracycline-induced decline in functional capacity and skeletal muscle injury compared to placebo.
Methods: PRADA II was a randomised, double-blind, placebo-controlled multicentre trial including 138 women with early breast cancer receiving (neo)adjuvant anthracycline therapy±trastuzumab. Participants were randomised prior to anthracycline initiation to sacubitril/valsartan or placebo for 18 months. The predefined primary outcome of this substudy was change in maximal handgrip strength from baseline to 18 months. Secondary outcomes included changes in 6-minute walk distance and circulating creatine kinase (CK) and myoglobin concentrations. Assessments were performed at baseline, post-anthracycline (Visit 2), and at 18 months (Visit 3). Changes were analysed using generalised linear mixed models, and a two-sided alpha level of 0.05 was applied to the primary outcome of this predefined substudy.
Results: Maximal handgrip strength declined in both groups from baseline to Visit 2, with partial recovery at Visit 3 in the sacubitril/valsartan group and continued decline in the placebo group. No significant between-group difference was observed in handgrip strength (between-group change from baseline to Visit 3: -0.3 kg, 95% CI -1.5 to 0.8, p=0.57). However, a greater decline from baseline to Visit 2 was observed with sacubitril/valsartan than placebo, corresponding to a between-group difference of -1.8 kg, 95% CI -3.0 to -0.6. 6-minute walk distance increased from baseline to both follow-up timepoints in the sacubitril/valsartan group, and a transient reduction was observed in the placebo group from baseline to Visit 2. Between-group changes did not differ at Visit 2 (8.8 m, 95% CI -19.3 to 36.9) or Visit 3 (13.6 m, 95% CI -13.3 to 40.5). CK and myoglobin were numerically higher in the placebo group from baseline to Visit 3, however, the confidence intervals for between-group differences included the null value (CK geometric mean ratio 1.17, 95% CI 0.94 to 1.45; myoglobin 1.10, 95% CI 0.98 to 1.23). Temporal changes by randomisation group are shown in Figure 1.
Conclusions: Sacubitril/valsartan did not significantly attenuate anthracycline-related decline in functional capacity assessed by maximal handgrip strength and 6-minute walk distance or changes in biomarkers of skeletal muscle injury. These findings suggest a neutral effect of sacubitril/valsartan on functional capacity, without challenging its potential cardioprotective role during anthracycline therapy.
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Gynnild, Mari Nordbø; Gulati, Geeta; Mecinaj, Albulena; Wethal, Torgeir; Holte, Espen & Vinje-Jakobsen, Victoria
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(2026).
Baseline and early changes in cardiac biomarkers as predictors of global longitudinal strain deterioration during breast cancer therapy: a PRADAII substudy.
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Background: Cardiac biomarkers are recommended for risk stratification before and during potentially cardiotoxic cancer therapy, but the prognostic value of baseline levels and early changes for subsequent left ventricular (LV) dysfunction remains unclear.
Objectives:
To evaluate whether baseline and early changes in high-sensitivity cardiac troponins (hs-cTnI, hs-cTnT) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) predict changes in global longitudinal strain (GLS) over 18 months.
Methods:
In the randomized PRADAII, 138 women treated with anthracyclines (±trastuzumab) received sacubitril/valsartan or placebo and underwent serial biomarker sampling and cardiac imaging at baseline, post-anthracycline, and 18 months. Longitudinal changes in GLS and left ventricular ejection fraction (LVEF) were analyzed using adjusted linear mixed models, including exploratory analyses of combined, persistent, and peak biomarker elevations.
Results:
Mean age was 54.0±9.4 years. At baseline, no patients had hs-cTnI values above the sex-specific 99th percentile, 6 (4%) had hs-cTnT >99th percentile, and 16 (12%) had NT-proBNP >125 ng/L. Mean baseline GLS was −19.5±2.1% and CMR- and echocardiography-derived LVEF was 60.3±4.8% and 58.3±6.2%, respectively. GLS declined modestly over follow-up, with less deterioration in the sacubitril/valsartan group than in the placebo group (ΔΔ −1.26, 95% CI −2.19 to −0.33).
Both hs-cTnI and hs-cTnT increased markedly after anthracycline therapy, with 16.7% and 71.7% exceeding the sex-specific 99th percentile at peak, whereas NT-proBNP showed modest changes with wide inter-individual variability. Transient and persistent troponin elevation occurred in 60.1% and 11.6%, respectively; corresponding NT-proBNP elevations in 5.1% and 7.3%, and combined troponin and NT-proBNP elevation in 9.4%.
Baseline biomarker levels were not associated with GLS deterioration, and no biomarker–treatment interactions were observed (all p for interaction >0.27). Early post-anthracycline changes in hs-cTnI, hs-cTnT, or NT-proBNP were not predictive of subsequent GLS decline, nor were peak or persistent elevations (Table 1, Figure 1). No significant associations were observed between baseline or early biomarker levels and changes in LVEF assessed by echocardiography or CMR.
Conclusions:
In our breast cancer cohort with preserved baseline LV function, baseline levels and early changes in hs-cTnI, hs-cTnT, and NT-proBNP were not associated with subsequent deterioration in GLS over 18 months. Larger studies including higher-risk patients and clinical endpoints are needed to clarify the role of cardiac biomarkers in individualized cardiotoxicity risk stratification.
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Gynnild, Mari Nordbø; Gulati, Geeta; Mecinaj, Albulena; Wethal, Torgeir; Holte, Espen & Vinje-Jakobsen, Victoria
[Show all 11 contributors for this article]
(2026).
Baseline and early changes in cardiac biomarkers as predictors of global longitudinal strain deterioration during breast cancer therapy: a PRADAII substudy.
European Heart Journal, Supplement.
ISSN 1520-765X.
28(Supplement_8).
doi:
10.1093/eurheartjsupp/suag097.089.
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Abstract Background Cardiac biomarkers are recommended for risk stratification before and during potentially cardiotoxic cancer therapy, but the prognostic value of baseline levels and early changes for subsequent left ventricular (LV) dysfunction remains unclear. Objectives To evaluate wheter baseline and early changes in high-sensitivity cardiac troponins (hs-cTnI, hs-cTnT) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) predict changes in global longitudinal strain (GLS) over 18 months. Methods In the randomized PRADAII, 138 women treated with anthracyclines (±trastuzumab) received sacubitril/valsartan or placebo and underwent serial biomarker sampling and cardiac imaging at baseline, post-anthracycline, and 18 months. Longitudinal changes in GLS and left ventricular ejection fraction (LVEF) were analyzed using adjusted linear mixed models, including exploratory analyses of combined, persistent, and peak biomarker elevations. Results Mean age was 54.0±9.4 years. At baseline, no patients had hs-cTnI values above the sex-specific 99th percentile, 6 (4%) had hs-cTnT >99th percentile, and 16 (12%) had NT-proBNP >125 ng/L. Mean baseline GLS was −19.5±2.1% and CMR- and echocardiography-derived LVEF was 60.3±4.8% and 58.3±6.2%, respectively. GLS declined modestly over follow-up, with less deterioration in the sacubitril/valsartan group than in the placebo group (ΔΔ −1.26, 95% CI −2.19 to −0.33). Both hs-cTnI and hs-cTnT increased markedly after anthracycline therapy, with 16.7% and 71.7% exceeding the sex-specific 99th percentile at peak, whereas NT-proBNP showed modest changes with wide inter-individual variability. Transient and persistent troponin elevation occurred in 60.1% and 11.6%, respectively; corresponding NT-proBNP elevations in 5.1% and 7.3%, and combined troponin and NT-proBNP elevation in 9.4%. Baseline biomarker levels were not associated with GLS deterioration, and no biomarker–treatment interactions were observed (all p for interaction >0.27). Early post-anthracycline changes in hs-cTnI, hs-cTnT, or NT-proBNP were not predictive of subsequent GLS decline, nor were peak or persistent elevations (Table 1, Figure 1). No significant associations were observed between baseline or early biomarker levels and changes in LVEF assessed by echocardiography or CMR. Conclusions In our breast cancer cohort with preserved baseline LV function, baseline levels and early changes in hs-cTnI, hs-cTnT, and NT-proBNP were not associated with subsequent deterioration in GLS over 18 months. Larger studies including higher-risk patients and clinical endpoints are needed to clarify the role of cardiac biomarkers in individualized cardiotoxicity risk stratification.
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Moen, Oda Klavestad; Johannessen, Øyvind; Myhre, Peder Langeland; Heck, Siri Lagethon; Corbett, Rebecca Aure & Windstad, Vilde Malo
[Show all 10 contributors for this article]
(2025).
Pre-test probability (PTP) for coronary artery disease (CAD) is enhanced by incorporating risk factors and coronary artery calcium (CAC) score.
European Society of Cardiology.
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Vinje, Victoria; Cao, Shu-qin; Heck, Siri Lagethon; Wisløff, Torbjørn; Klæboe, Lars Gunnar & Nilsen, Hilde Loge
[Show all 9 contributors for this article]
(2023).
Rationale And Design Of The NARNIA Trial: The Effect Of NicotinAmide Riboside ON Myocardial And Skeletal Muscle Injury And Function In Patients With Metastatic Breast Cancer Receiving Anthracyclines.
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Heck, Siri Lagethon; Gulati, Geeta; HOFFMANN, PAVEL; Knobelsdorff-Brenkenhoff, Florian von; Storås, Tryggve & Ree, Anne Hansen
[Show all 11 contributors for this article]
(2016).
Effects of Candesartan and Metoprolol on Myocardial Mass, Edema, and Fibrosis During Anthracycline Treatment in Early Breast Cancer: APRADA-CMR substudy.
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Gulati, Geeta; Heck, Siri Lagethon; HOFFMANN, PAVEL; Ree, Anne Hansen; Schulz-Menger, Jeanette & Knobelsdorff-Brenkenhoff, Florian von
[Show all 12 contributors for this article]
(2016).
Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Primary Results of a Randomized, 2 x 2 Factorial, Placebo-Controlled, Double-Blind Clinical Trial.
Circulation.
ISSN 0009-7322.
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Heck, Siri Lagethon; Gulati, Geeta; Knobelsdorff-Brenkenhoff, Florian von; Storås, Trygve H; Schulz-Menger, Jeanette & HOFFMANN, PAVEL
[Show all 7 contributors for this article]
(2016).
Validation of myocardial extracellular volume equation by serial cardiac magnetic resonance imaging measurements in patients with varying hematocrit.
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Gulati, Geeta; Heck, Siri Lagethon; Geisler, Jürgen; Fagerland, Morten; HOFFMANN, PAVEL & Gravdehaug, Berit
[Show all 10 contributors for this article]
(2016).
Effect of candesartan and metoprolol on subclinical myocardial injury during anthracycline therapy: data from the prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA) study.
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Published
Aug. 15, 2023 3:07 PM
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Oct. 30, 2023 5:20 PM
