Publications by authors named "Antti Saraste"

224 Publications

Multimodality imaging approach to left ventricular dysfunction in diabetes: an expert consensus document from the European Association of Cardiovascular Imaging.

Authors:
Thomas H Marwick Alessia Gimelli Sven Plein Jeroen J Bax Phillippe Charron Victoria Delgado Erwan Donal Patrizio Lancellotti Eylem Levelt Pal Maurovich-Horvat Stefan Neubauer Gianluca Pontone Antti Saraste Bernard Cosyns Thor Edvardsen Bogdan A Popescu Maurizio Galderisi Genevieve Derumeaux Magnus Bäck Philippe B Bertrand Marc Dweck Niall Keenan Julien Magne Danilo Neglia Ivan Stankovic

Eur Heart J Cardiovasc Imaging 2021 Nov 5. Epub 2021 Nov 5.

IMRB - Inserm U955 Senescence, metabolism and cardiovascular diseases 8, rue du Général Sarrail, 94010 Créteil, France.

Heart failure (HF) is among the most important and frequent complications of diabetes mellitus (DM). The detection of subclinical dysfunction is a marker of HF risk and presents a potential target for reducing incident HF in DM. Left ventricular (LV) dysfunction secondary to DM is heterogeneous, with phenotypes including predominantly systolic, predominantly diastolic, and mixed dysfunction. Indeed, the pathogenesis of HF in this setting is heterogeneous. Effective management of this problem will require detailed phenotyping of the contributions of fibrosis, microcirculatory disturbance, abnormal metabolism, and sympathetic innervation, among other mechanisms. For this reason, an imaging strategy for the detection of HF risk needs to not only detect subclinical LV dysfunction (LVD) but also characterize its pathogenesis. At present, it is possible to identify individuals with DM at increased risk HF, and there is evidence that cardioprotection may be of benefit. However, there is insufficient justification for HF screening, because we need stronger evidence of the links between the detection of LVD, treatment, and improved outcome. This review discusses the options for screening for LVD, the potential means of identifying the underlying mechanisms, and the pathways to treatment.
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http://dx.doi.org/10.1093/ehjci/jeab220DOI Listing
November 2021

Effect of respiratory motion correction and CT-based attenuation correction on dual-gated cardiac PET image quality and quantification.

Authors:
Jussi Schultz Reetta Siekkinen Mojtaba Jafari Tadi Mika Teräs Riku Klén Eero Lehtonen Antti Saraste Jarmo Teuho

J Nucl Cardiol 2021 Sep 3. Epub 2021 Sep 3.

Turku PET Centre, Turku University Hospital, Kiinamyllynkatu 4-8, 20521, Turku, Finland.

Background: Dual-gating reduces respiratory and cardiac motion effects but increases noise. With motion correction, motion is minimized and image quality preserved. We applied motion correction to create end-diastolic respiratory motion corrected images from dual-gated images.

Methods: [F]-fluorodeoxyglucose ([F]-FDG) PET images of 13 subjects were reconstructed with 4 methods: non-gated, dual-gated, motion corrected, and motion corrected with 4D-CT (MoCo-4D). Image quality was evaluated using standardized uptake values, contrast ratio, signal-to-noise ratio, coefficient of variation, and contrast-to-noise ratio. Motion minimization was evaluated using myocardial wall thickness.

Results: MoCo-4D showed improvement for contrast ratio (2.83 vs 2.76), signal-to-noise ratio (27.5 vs 20.3) and contrast-to-noise ratio (14.5 vs 11.1) compared to dual-gating. The uptake difference between MoCo-4D and non-gated images was non-significant (P > .05) for the myocardium (2.06 vs 2.15 g/mL), but significant (P < .05) for the blood pool (.80 vs .86 g/mL). Non-gated images had the lowest coefficient of variation (27.3%), with significant increase for all other methods (31.6-32.5%). MoCo-4D showed smallest myocardial wall thickness (16.6 mm) with significant decrease compared to non-gated images (20.9 mm).

Conclusions: End-diastolic respiratory motion correction and 4D-CT resulted in improved motion minimization and image quality over standard dual-gating.
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http://dx.doi.org/10.1007/s12350-021-02769-6DOI Listing
September 2021

Quantitative myocardial perfusion response to adenosine and regadenoson in patients with suspected coronary artery disease.

Authors:
Tanja Kero Antti Saraste Bo Lagerqvist Jens Sörensen Essi Pikkarainen Mark Lubberink Juhani Knuuti

J Nucl Cardiol 2021 Aug 12. Epub 2021 Aug 12.

Turku PET Centre, Turku, Finland.

Background: The aim of the present study was to compare the quantitative flow responses of regadenoson against adenosine using cardiac O-water PET imaging in patients with suspected or known coronary artery disease (CAD).

Methods: Hyperemic myocardial blood flow (MBF) after adenosine and regadenoson was compared using correlation and Bland-Altman analysis in 21 patients who underwent rest and adenosine O-water PET scans followed by rest and regadenoson O-water PET scans.

Results: Global mean (± SD) MBF values at rest and stress were 0.92 ± 0.27 and 2.68 ± 0.80 mL·g·min for the adenosine study and 0.95 ± 0.29 and 2.76 ± 0.79 mL·g·min for the regadenoson study (P = 0.55 and P = 0.49). The correlations between global and regional adenosine- and regadenoson-based stress MBF were strong (r = 0.80 and r = 0.77). The biases were small for both global and regional MBF comparisons (0.08 and 0.09 mL·min·g), but the limits of agreement were wide for stress MBF.

Conclusion: The correlation between regadenoson- and adenosine-induced hyperemic MBF was strong but the agreement was only moderate indicating that established cut-off values for 0-water PET should be used cautiously if using regadenoson as vasodilator.
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http://dx.doi.org/10.1007/s12350-021-02731-6DOI Listing
August 2021

Effect of Inhaled Xenon on Cardiac Function in Comatose Survivors of Out-of-Hospital Cardiac Arrest-A Substudy of the Xenon in Combination With Hypothermia After Cardiac Arrest Trial.

Authors:
Antti Saraste Haitham Ballo Olli Arola Ruut Laitio Juhani Airaksinen Marja Hynninen Minna Bäcklund Emmi Ylikoski Johanna Wennervirta Mikko Pietilä Risto O Roine Veli-Pekka Harjola Jussi Niiranen Kirsi Korpi Marjut Varpula Harry Scheinin Mervyn Maze Tero Vahlberg Timo Laitio

Crit Care Explor 2021 Aug 29;3(8):e0502. Epub 2021 Jul 29.

Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, University of Turku, Turku, Finland.

This explorative substudy aimed at determining the effect of inhaled xenon on left ventricular function by echocardiography in comatose survivors of out-of-hospital cardiac arrest.

Design: A randomized two-group single-blinded phase 2 clinical drug trial.

Setting: A multipurpose ICU in two university hospitals.

Patients: Of the 110 randomized comatose survivors after out-of-hospital cardiac arrest with a shockable rhythm in the xenon in combination with hypothermia after cardiac arrest trial, 38 patients (24-76 yr old) with complete echocardiography were included in this study.

Interventions: Patients were randomized to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours or hypothermia treatment alone. Echocardiography was performed at hospital admission and 24 ± 4 hours after hypothermia.

Measurements And Main Results: Left ventricular ejection fraction, myocardial longitudinal systolic strain, and diastolic function were analyzed blinded to treatment. There were 17 xenon and 21 control patients in whom echocardiography was completed. Clinical characteristics did not differ significantly between the groups. At admission, ejection fraction was similar in xenon and control patients (39% ± 10% vs 38% ± 11%; = 0.711) but higher in xenon than control patients after hypothermia (50% ± 10% vs 42% ± 10%; = 0.014). Global longitudinal systolic strain was similar in xenon and control patients at admission (-9.0% ± 3.8% vs -8.1% ± 3.6%; = 0.555) but better in xenon than control patients after hypothermia (-14.4.0% ± 4.0% vs -10.5% ± 4.0%; = 0.006). In patients with coronary artery disease, longitudinal strain improved in the nonischemic myocardial segments in xenon patients. There were no changes in diastolic function between the groups.

Conclusions: Among comatose survivors of a cardiac cause out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia was associated with greater recovery of left ventricular systolic function in comparison with hypothermia alone.
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http://dx.doi.org/10.1097/CCE.0000000000000502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323798PMC
August 2021

Association between [Ga]NODAGA-RGDyK uptake and dynamics of angiogenesis in a human cell-based 3D model.

Authors:
Maria Grönman Olli Moisio Xiang-Guo Li Tarja Toimela Outi Huttala Tuula Heinonen Juhani Knuuti Anne Roivainen Antti Saraste

Mol Biol Rep 2021 Jun 2;48(6):5347-5353. Epub 2021 Jul 2.

Turku PET Centre, University of Turku, Turku, Finland.

Radiolabeled RGD peptides targeting expression of αβ integrin have been applied to in vivo imaging of angiogenesis. However, there is a need for more information on the quantitative relationships between RGD peptide uptake and the dynamics of angiogenesis. In this study, we sought to measure the binding of [Ga]NODAGA-RGDyK to αβ integrin in a human cell-based three-dimensional (3D) in vitro model of angiogenesis, and to compare the level of binding with the amount of angiogenesis. Experiments were conducted using a human cell-based 3D model of angiogenesis consisting of co-culture of human adipose stem cells (hASCs) and of human umbilical vein endothelial cells (HUVECs). Angiogenesis was induced with four concentrations (25%, 50%, 75%, and 100%) of growth factor cocktail resulting in a gradual increase in the density of the tubule network. Cultures were incubated with [Ga]NODAGA-RGDyK for 90 min at 37 °C, and binding of radioactivity was measured by gamma counting and digital autoradiography. The results revealed that tracer binding increased gradually with neovasculature density. In comparison with vessels induced with a growth factor concentration of 25%, the uptake of [Ga]NODAGA-RGDyK was higher at concentrations of 75% and 100%, and correlated with the amount of neovasculature, as determined by visual evaluation of histological staining. Uptake of [Ga]NODAGA-RGDyK closely reflected the amount of angiogenesis in an in vitro 3D model of angiogenesis. These results support further evaluation of RGD-based approaches for targeted imaging of angiogenesis.
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http://dx.doi.org/10.1007/s11033-021-06513-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318966PMC
June 2021

A Respiratory Motion Estimation Method Based on Inertial Measurement Units for Gated Positron Emission Tomography.

Authors:
Eero Lehtonen Jarmo Teuho Juho Koskinen Mojtaba Jafari Tadi Riku Klén Reetta Siekkinen Joaquin Rives Gambin Tuija Vasankari Antti Saraste

Sensors (Basel) 2021 Jun 9;21(12). Epub 2021 Jun 9.

Turku PET Centre, University of Turku and Turku University Hospital, 20521 Turku, Finland.

We present a novel method for estimating respiratory motion using inertial measurement units (IMUs) based on microelectromechanical systems (MEMS) technology. As an application of the method we consider the amplitude gating of positron emission tomography (PET) imaging, and compare the method against a clinically used respiration motion estimation technique. The presented method can be used to detect respiratory cycles and estimate their lengths with state-of-the-art accuracy when compared to other IMU-based methods, and is the first based on commercial MEMS devices, which can estimate quantitatively both the magnitude and the phase of respiratory motion from the abdomen and chest regions. For the considered test group consisting of eight subjects with acute myocardial infarction, our method achieved the absolute breathing rate error per minute of 0.44 ± 0.23 1/min, and the absolute amplitude error of 0.24 ± 0.09 cm, when compared to the clinically used respiratory motion estimation technique. The presented method could be used to simplify the logistics related to respiratory motion estimation in PET imaging studies, and also to enable multi-position motion measurements for advanced organ motion estimation.
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http://dx.doi.org/10.3390/s21123983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228885PMC
June 2021

Extensive and balanced reduction of myocardial blood flow in patients with suspected obstructive coronary artery disease: 15O-water PET study.

Authors:
Teemu Maaniitty Iida Stenström Antti Saraste Juhani Knuuti

Int J Cardiol 2021 09 16;338:1-7. Epub 2021 Jun 16.

Turku PET Centre, University of Turku, Turku, Finland; Department of Clinical Physiology, Nuclear Medicine and PET, Turku University Hospital, Turku, Finland.

Background: Detection of obstructive coronary artery disease (CAD) by stress myocardial perfusion imaging (MPI) is conventionally based on relative differences in perfusion. This may lead to either underestimation of the extent of myocardial ischemia, or the ischemia might be completely missed in case of balanced perfusion reduction. Using absolute quantification of myocardial blood flow (MBF) by positron emission tomography (PET), we evaluated how common are extensive and balanced myocardial perfusion abnormalities in symptomatic patients with suspected obstructive CAD.

Methods And Results: Among 758 consecutive symptomatic patients undergone coronary computed tomography angiography (CTA), 286 patients subsequently underwent quantitative 15O-water adenosine-stress PET MPI to assess the hemodynamic significance of suspected obstructive stenosis. Out of these, 46 (16%) patients had reduced (≤2.3 ml/g/min) absolute stress MBF in all three standard coronary territories (LAD, LCX, RCA). Subsequently, relative stress MBF in each coronary territory was calculated, considering a territory with the highest absolute stress MBF as a reference region. Among the 46 patients, 72% had significant regional heterogeneity in myocardial perfusion (defined as having ≥1 territory with relative stress MBF <80%) while the remaining 28% (4.5% of the whole MPI cohort) showed balanced perfusion reduction (all relative MBF values ≥80%).

Conclusions: Among symptomatic patients with suspected obstructive stenosis on coronary CTA, quantitative PET revealed that 16% of patients had reduced stress MBF involving all three coronary artery territories, of whom approximately one third showed balanced reduction. Thus, in 4.5% of the patients the perfusion abnormalities could have been missed by conventional relative MPI analysis.
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http://dx.doi.org/10.1016/j.ijcard.2021.06.012DOI Listing
September 2021

Stress myocardial blood flow and revascularization in chronic coronary artery disease.

Authors:
Teemu Maaniitty Juhani Knuuti Antti Saraste

J Nucl Cardiol 2021 Jun 8. Epub 2021 Jun 8.

Turku PET Centre, Turku University Hospital and University of Turku, Turku, Finland.

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http://dx.doi.org/10.1007/s12350-021-02687-7DOI Listing
June 2021

Cardiac perfusion by positron emission tomography.

Authors:
Wail Nammas Teemu Maaniitty Juhani Knuuti Antti Saraste

Clin Physiol Funct Imaging 2021 Sep 25;41(5):385-400. Epub 2021 May 25.

Heart Center, Turku University Hospital, Turku, Finland.

Myocardial perfusion imaging (MPI) with positron emission tomography (PET) is an established tool for evaluation of obstructive coronary artery disease (CAD). The contemporary 3-dimensional scanner technology and the state-of-the-art MPI radionuclide tracers and pharmacological stress agents, as well as the cutting-edge image reconstruction techniques and data analysis software, have all enabled accurate, reliable and reproducible quantification of absolute myocardial blood flow (MBF), and henceforth calculation of myocardial flow reserve (MFR) in several clinical scenarios. In patients with suspected coronary artery disease, both absolute stress MBF and MFR can identify myocardial territories subtended by epicardial coronary arteries with haemodynamically significant stenosis, as defined by invasive coronary fractional flow reserve measurement. In particular, absolute stress MBF and MFR offered incremental prognostic information for predicting adverse cardiac outcome, and hence for better patient risk stratification, over those provided by traditional clinical risk predictors. This article reviews the available evidence to support the translation of the current techniques and technologies into a useful decision-making tool in real-world clinical practice.
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http://dx.doi.org/10.1111/cpf.12708DOI Listing
September 2021

Assessment of a digital and an analog PET/CT system for accurate myocardial perfusion imaging with a flow phantom.

Authors:
Reetta Siekkinen Anna K Kirjavainen Kalle Koskensalo Nadia A S Smith Andrew Fenwick Virva Saunavaara Tuula Tolvanen Hidehiro Iida Antti Saraste Mika Teräs Jarmo Teuho

J Nucl Cardiol 2021 May 4. Epub 2021 May 4.

Turku PET Centre, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, Turku, 20521, Finland.

In Myocardial Perfusion Imaging (MPI) with Positron Emission Tomography/Computed Tomography (PET/CT) systems, accurate quantification is essential. We assessed flow quantification accuracy over various injected activities using a flow phantom.

Methods: The study was performed on the digital 4-ring Discovery MI (DMI-20) and analog Discovery 690 (D690) PET/CT systems, using 325-1257 MBq of [O]HO. PET performance and flow quantification accuracy were assessed in terms of count-rates, dead-time factors (DTF), scatter fractions (SF), time-activity curves (TACs), areas-under-the-curves (AUCs) and flow values.

Results: On DMI-20, prompts of 12.8 Mcps, DTF of 2.06 and SF of 46.1% were measured with 1257 MBq of activity. On the D690, prompts of 6.85 Mcps, DTF of 1.57 and SF of 32.5% were measured with 1230 MBq of activity. AUC values were linear over all activities. Mean wash-in flow error was - 9% for both systems whereas wash-out flow error was - 5% and - 6% for DMI-20 and D690. With the highest activity, wash-out flow error was - 12% and - 7% for the DMI-20 and D690.

Conclusion: DMI-20 and D690 preserved accurate flow quantification over all injected activities, with maximum error of - 12%. In the future, flow quantification accuracy over the activities and count-rates evaluated in this study should be assessed.
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http://dx.doi.org/10.1007/s12350-021-02631-9DOI Listing
May 2021

Position paper of the EACVI and EANM on artificial intelligence applications in multimodality cardiovascular imaging using SPECT/CT, PET/CT, and cardiac CT.

Authors:
Riemer H J A Slart Michelle C Williams Luis Eduardo Juarez-Orozco Christoph Rischpler Marc R Dweck Andor W J M Glaudemans Alessia Gimelli Panagiotis Georgoulias Olivier Gheysens Oliver Gaemperli Gilbert Habib Roland Hustinx Bernard Cosyns Hein J Verberne Fabien Hyafil Paola A Erba Mark Lubberink Piotr Slomka Ivana Išgum Dimitris Visvikis Márton Kolossváry Antti Saraste

Eur J Nucl Med Mol Imaging 2021 05 17;48(5):1399-1413. Epub 2021 Apr 17.

Turku PET Centre, Turku University Hospital, University of Turku, Turku, Finland.

In daily clinical practice, clinicians integrate available data to ascertain the diagnostic and prognostic probability of a disease or clinical outcome for their patients. For patients with suspected or known cardiovascular disease, several anatomical and functional imaging techniques are commonly performed to aid this endeavor, including coronary computed tomography angiography (CCTA) and nuclear cardiology imaging. Continuous improvement in positron emission tomography (PET), single-photon emission computed tomography (SPECT), and CT hardware and software has resulted in improved diagnostic performance and wide implementation of these imaging techniques in daily clinical practice. However, the human ability to interpret, quantify, and integrate these data sets is limited. The identification of novel markers and application of machine learning (ML) algorithms, including deep learning (DL) to cardiovascular imaging techniques will further improve diagnosis and prognostication for patients with cardiovascular diseases. The goal of this position paper of the European Association of Nuclear Medicine (EANM) and the European Association of Cardiovascular Imaging (EACVI) is to provide an overview of the general concepts behind modern machine learning-based artificial intelligence, highlights currently prefered methods, practices, and computational models, and proposes new strategies to support the clinical application of ML in the field of cardiovascular imaging using nuclear cardiology (hybrid) and CT techniques.
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http://dx.doi.org/10.1007/s00259-021-05341-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113178PMC
May 2021

Evaluation of glucagon-like peptide-1 receptor expression in nondiabetic and diabetic atherosclerotic mice using PET tracer Ga-NODAGA-exendin-4.

Authors:
Mia Ståhle Sanna Hellberg Jenni Virta Heidi Liljenbäck Olli Metsälä Xiang-Guo Li Matti Jauhiainen Pekka Saukko Seppo Ylä-Herttuala Pirjo Nuutila Juhani Knuuti Antti Saraste Anne Roivainen

Am J Physiol Endocrinol Metab 2021 05 12;320(5):E989-E998. Epub 2021 Apr 12.

Turku PET Centre, University of Turku, Turku, Finland.

Cardiovascular effects of glucagon-like peptide-1 receptor (GLP-1R) agonist therapies are potentially mediated by anti-inflammatory effects on atherosclerosis. Our study demonstrates that Ga-NODAGA-exendin-4, a radioligand specifically targeting GLP-1R, detects GLP-1R expression in inflamed atherosclerotic lesions in nondiabetic and diabetic hypercholesterolemic mice. Immunofluorescence staining suggests that GLP-1R is primarily localized in M2 macrophages in lesions. This study describes a new potential tool that may have translational relevance for studies of pharmacological modification of GLP-1R signaling in atherosclerosis.
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http://dx.doi.org/10.1152/ajpendo.00465.2020DOI Listing
May 2021

Improving patient identification for advanced cardiac imaging through machine learning-integration of clinical and coronary CT angiography data.

Authors:
Jan Walter Benjamins Ming Wai Yeung Teemu Maaniitty Antti Saraste Riku Klén Pim van der Harst Juhani Knuuti Luis Eduardo Juarez-Orozco

Int J Cardiol 2021 07 6;335:130-136. Epub 2021 Apr 6.

University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, 9700RB Groningen, the Netherlands; Turku PET Centre, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20520 Turku, Finland; Department of Cardiology, Hart and Lung Division, University Medical Centre Utrecht, Heidelberglaan 100, 3508, GA, Utrecht, the Netherlands. Electronic address:

Background: Standard computed tomography angiography (CTA) outputs a myriad of interrelated variables in the evaluation of suspected coronary artery disease (CAD). But an important proportion of obstructive lesions does not cause significant myocardial ischemia. Nowadays, machine learning (ML) allows integration of numerous variables through complex interdependencies that optimize classification and prediction at the individual level. We evaluated ML performance in integrating CTA and clinical variables to identify patients that demonstrate myocardial ischemia through PET and those who ultimately underwent early revascularization.

Methods And Results: 830 patients with CTA and selective PET were analyzed. Nine clinical and 58 CTA variables were integrated through ensemble-boosting ML to identify patients with ischemia and those who underwent early revascularization. ML performance was compared against expert CTA interpretation, calcium score and clinical variables. While ML using all CTA variables achieved an AUC = 0.85, it was outperformed by expert CTA interpretation (AUC = 0.87, p < 0.01 for comparison), comparable to ML integration of CTA variables with clinical variables. However, the best performance was achieved by ML integration of expert CTA interpretation and clinical variables for both dependent variables (AUCs = 0.91 and 0.90, p < 0.001).

Conclusions: Machine learning integration of diagnostic CTA and clinical data may improve identification of patients with myocardial ischemia and those requiring early revascularization at the individual level. This could potentially aid in sparing the need for subsequent advanced imaging and better identifying patients in ultimate need for revascularization. While ML integrating all CTA variables did not outperform expert CTA interpretation, ML data integration from different sources consistently improves diagnostic performance.
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http://dx.doi.org/10.1016/j.ijcard.2021.04.009DOI Listing
July 2021

Sex differences in coronary plaque changes assessed by serial computed tomography angiography.

Authors:
Mohammed El Mahdiui Jeff M Smit Alexander R van Rosendael Danilo Neglia Juhani Knuuti Antti Saraste Ronny R Buechel Anna Teresinska Maria N Pizzi Albert Roque Massimo Magnacca Bart J Mertens Chiara Caselli Silvia Rocchiccioli Oberdan Parodi Gualtiero Pelosi Arthur J Scholte

Int J Cardiovasc Imaging 2021 Jul 10;37(7):2311-2321. Epub 2021 Mar 10.

Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.

Long-term data on sex-differences in coronary plaque changes over time is lacking in a low-to-intermediate risk population of stable coronary artery disease (CAD). The aim of this study was to evaluate the role of sex on long-term plaque progression and evolution of plaque composition. Furthermore, the influence of menopause on plaque progression and composition was also evaluated. Patients that underwent a coronary computed tomography angiography (CTA) were prospectively included to undergo a follow-up coronary CTA. Total and compositional plaque volumes were normalized using the vessel volume to calculate a percentage atheroma volume (PAV). To investigate the influence of menopause on plaque progression, patients were divided into two groups, under and over 55 years of age. In total, 211 patients were included in this analysis, 146 (69%) men. The mean interscan period between baseline and follow-up coronary CTA was 6.2 ± 1.4 years. Women were older, had higher HDL levels and presented more often with atypical chest pain. Men had 434 plaque sites and women 156. On a per-lesion analysis, women had less fibro-fatty PAV compared to men (β -1.3 ± 0.4%; p < 0.001), with no other significant differences. When stratifying patients by 55 years age threshold, fibro-fatty PAV remained higher in men in both age groups (p < 0.05) whilst women younger than 55 years demonstrated more regression of fibrous (β -0.8 ± 0.3% per year; p = 0.002) and non-calcified PAV (β -0.7 ± 0.3% per year; p = 0.027). In a low-to-intermediate risk population of stable CAD patients, no significant sex differences in total PAV increase over time were observed. Fibro-fatty PAV was lower in women at any age and women under 55 years demonstrated significantly greater reduction in fibrous and non-calcified PAV over time compared to age-matched men. (ClinicalTrials.gov number, NCT04448691.).
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http://dx.doi.org/10.1007/s10554-021-02204-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286938PMC
July 2021

Disproportionate left atrial myopathy in heart failure with preserved ejection fraction among participants of the PROMIS-HFpEF study.

Authors:
Ravi B Patel Carolyn S P Lam Sara Svedlund Antti Saraste Camilla Hage Ru-San Tan Lauren Beussink-Nelson Jasper Tromp Cynthia Sanchez Joyce Njoroge Stanley A Swat Ulrika Ljung Faxén Maria Lagerstrom Fermer Ashwin Venkateshvaran Li-Ming Gan Lars H Lund Sanjiv J Shah

Sci Rep 2021 03 1;11(1):4885. Epub 2021 Mar 1.

Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Impaired left atrial (LA) function in heart failure with preserved ejection fraction (HFpEF) is associated with adverse outcomes. A subgroup of HFpEF may have LA myopathy out of proportion to left ventricular (LV) dysfunction; therefore, we sought to characterize HFpEF patients with disproportionate LA myopathy. In the prospective, multicenter, Prevalence of Microvascular Dysfunction in HFpEF study, we defined disproportionate LA myopathy based on degree of LA reservoir strain abnormality in relation to LV myopathy (LV global longitudinal strain [GLS]) by calculating the residuals from a linear regression of LA reservoir strain and LV GLS. We evaluated associations of disproportionate LA myopathy with hemodynamics and performed a plasma proteomic analysis to identify proteins associated with disproportionate LA myopathy; proteins were validated in an independent sample. Disproportionate LA myopathy correlated with better LV diastolic function but was associated with lower stroke volume reserve after passive leg raise independent of atrial fibrillation (AF). Additionally, disproportionate LA myopathy was associated with higher pulmonary artery systolic pressure, higher pulmonary vascular resistance, and lower coronary flow reserve. Of 248 proteins, we identified and validated 5 proteins (involved in cardiomyocyte stretch, extracellular matrix remodeling, and inflammation) that were associated with disproportionate LA myopathy independent of AF. In HFpEF, LA myopathy may exist out of proportion to LV myopathy. Disproportionate LA myopathy is a distinct HFpEF subtype associated with worse hemodynamics and a distinct proteomic signature, independent of AF.
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http://dx.doi.org/10.1038/s41598-021-84133-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921666PMC
March 2021

Generalizability of HFA-PEFF and HFPEF Diagnostic Algorithms and Associations With Heart Failure Indices and Proteomic Biomarkers: Insights From PROMIS-HFpEF.

Authors:
U L Faxen Ashwin Venkateshvaran Sanjiv J Shah Carolyn S P Lam Sara Svedlund Antti Saraste Lauren Beussink-Nelson Maria Lagerstrom Fermer Li-Ming Gan Camilla Hage Lars H Lund

J Card Fail 2021 07 26;27(7):756-765. Epub 2021 Feb 26.

Department of Medicine, Cardiology Unit, Karolinska Institutet, Stockholm, Sweden.

Background: Diagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging. We aimed to evaluate the generalizability of the HFA-PEFF (Heart Failure Association Pre-test assessment, Echocardiography & natriuretic peptide, Functional testing, Final etiology) and weighted HFPEF (Heavy, 2 or more Hypertensive drugs, atrial Fibrillation, Pulmonary hypertension, Elder age > 60, elevated Filling pressures) diagnostic algorithms and associations with HF severity, coronary microvascular dysfunction and proteomic biomarkers.

Methods And Results: Diagnostic likelihood of HFpEF was calculated in the prospective, multinational PROMIS-HFpEF (Prevalence of microvascular dysfunction in HFpEF) cohort using current European Society of Cardiology recommendations, HFA-PEFF and HFPEF algorithms. Associations between the 2 algorithms and left atrial function, Doppler-based coronary flow reserve, 6-minute walk test, quality of life, and proteomic biomarkers were investigated. Of 181 patients with an EF of ≥50%, 129 (71%) and 94 (52%) fulfilled criteria for high likelihood HFpEF as per HFA-PEFF and HFPEF, and 28% and 46% were classified as intermediate likelihood, requiring additional hemodynamic testing. High likelihood HFpEF patients were older with higher prevalence of atrial fibrillation and lower global longitudinal strain and left atrial reservoir strain (P < .001 for all variables). left atrial reservoir strain and global longitudinal strain were inversely associated with both HFA-PEFF and HFPEF scores (TauB = -0.35 and -0.46 and -0.21 and -0.31; P < .001 for all). There were no associations between scoring and 6-minute walk test, quality of life, and coronary flow reserve. Both scores were associated with biomarkers related to inflammation, oxidative stress, and fibrosis.

Conclusions: Although the HFA-PEFF and HFPEF scores were associated with measures of HF severity and biomarkers related to HFpEF, they demonstrated a modest and differential ability to identify HFpEF noninvasively, necessitating additional functional testing to confirm the diagnosis.
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http://dx.doi.org/10.1016/j.cardfail.2021.02.005DOI Listing
July 2021

Let it be: fate of a lost closure device.

Authors:
K E Juhani Airaksinen Juha Lund Antti Saraste

Eur Heart J 2021 Feb 5. Epub 2021 Feb 5.

Heart Centre, Turku University Hospital and University of Turku, POB 52, FI-20521 Turku, Finland.

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http://dx.doi.org/10.1093/eurheartj/ehab046DOI Listing
February 2021

The role of myocardial innervation imaging in different clinical scenarios: an expert document of the European Association of Cardiovascular Imaging and Cardiovascular Committee of the European Association of Nuclear Medicine.

Authors:
Alessia Gimelli Riccardo Liga Denis Agostini Frank M Bengel Sabine Ernst Fabien Hyafil Antti Saraste Arthur J H A Scholte Hein J Verberne Derk O Verschure Riemer H J A Slart

Eur Heart J Cardiovasc Imaging 2021 04;22(5):480-490

Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Centre, University Medical Center Groningen, Groningen, The Netherlands.

Cardiac sympathetic activity plays a key role in supporting cardiac function in both health and disease conditions, and nuclear cardiac imaging has always represented the only way for the non-invasive evaluation of the functional integrity of cardiac sympathetic terminals, mainly through the use of radiopharmaceuticals that are analogues of norepinephrine and, in particular, with the use of 123I-mIBG imaging. This technique demonstrates the presence of cardiac sympathetic dysfunction in different cardiac pathologies, linking the severity of sympathetic nervous system impairment to adverse patient's prognosis. This article will outline the state-of-the-art of cardiac 123I-mIBG imaging and define the value and clinical applications in the different fields of cardiovascular diseases.
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http://dx.doi.org/10.1093/ehjci/jeab007DOI Listing
April 2021

Efficacy and tolerability of folate-aminopterin therapy in a rat focal model of multiple sclerosis.

Authors:
Petri Elo Xiang-Guo Li Heidi Liljenbäck Maria Gardberg Olli Moisio Maxwell Miner Jenni Virta Antti Saraste Madduri Srinivasarao Michael Pugh Philip S Low Juhani Knuuti Sirpa Jalkanen Laura Airas Yingjuan June Lu Anne Roivainen

J Neuroinflammation 2021 Jan 20;18(1):30. Epub 2021 Jan 20.

Turku PET Centre, University of Turku, Turku, Finland.

Background: Activated macrophages in the experimental model of multiple sclerosis (MS) express folate receptor-β (FR-β), representing a promising target for the treatment of MS. Here, we both evaluated the efficacy of a novel folate-aminopterin construct (EC2319) in a rat focal model of multiple sclerosis (MS) and investigated the utility of Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate (Ga-FOL) for assessing inflammatory lesions. In addition, we investigated whether FR-β is expressed in the brain of patients with MS.

Methods: Focal delayed-type hypersensitivity experimental autoimmune encephalomyelitis (fDTH-EAE) was induced in 40 Lewis rats; 20 healthy Lewis rats were used as controls. Rats were divided into six groups according to the duration of disease (control, acute, or chronic) and intervention (vehicle versus EC2319). Ga-FOL analyses, histology, and immunofluorescence of the brain were performed to evaluate the efficacy of subcutaneously administered EC2319 on lesion development. Immunofluorescence was used to assess FR-β expression in postmortem brain samples from 5 patients with MS and 5 healthy controls.

Results: Immunofluorescence and histological analyses revealed significant reductions in FR-β expression (P < 0.05) and lesion size (P < 0.01), as well as improved inducible nitric oxide synthase/mannose receptor C type 1 ratios (P < 0.01) in macrophages and microglia during the chronic but not acute phase of fDTH-EAE in EC2319-treated rats. The uptake of IV-injected Ga-FOL in the brain was low and did not differ between the groups, but the in vitro binding of Ga-FOL was significantly lower in EC2319-treated rats (P < 0.01). FR-β positivity was observed in chronically active lesions and in normal-appearing white matter in MS brain samples.

Conclusions: EC2319 was well tolerated and attenuated inflammation and lesion development in a rat model of a chronic progressive form of MS. Human MS patients have FR-β-positive cells in chronically active plaques, which suggests that these results may have translational relevance.
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http://dx.doi.org/10.1186/s12974-021-02073-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819223PMC
January 2021

Prosthetic Valve Endocarditis: A Case Report with 18F-FDG-PET/CT as Part of the Diagnostic Workup.

Authors:
Soile Pauliina Salomäki Antti Saraste Päivi Jalava-Karvinen Laura Pirilä Ulla Hohenthal

Case Rep Cardiol 2020 26;2020:4921380. Epub 2020 Nov 26.

Department of infectious Diseases, Division of Medicine, Turku University Hospital, Turku, Finland.

Diagnosis of spp. infective endocarditis (IE) is challenging, and diagnostic delays are common. We describe two patients with spp. prosthetic valve endocarditis (PVE) and fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG-PET/CT) as a part of diagnostic workup. We also refer to 5 other cases we found from the published literature. These cases highlight that F-FDG-PET/CT can improve diagnostic accuracy in prosthetic valve endocarditis.
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http://dx.doi.org/10.1155/2020/4921380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714588PMC
November 2020

Quantitative PET Perfusion Imaging: How to Interpret the Results?

Authors:
Juhani Knuuti Antti Saraste

JACC Cardiovasc Imaging 2021 05 25;14(5):1035-1037. Epub 2020 Nov 25.

Turku PET Centre, Turku University Hospital and University of Turku, Turku, Finland; Heart Center, Turku University Hospital, Turku, Finland.

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http://dx.doi.org/10.1016/j.jcmg.2020.10.020DOI Listing
May 2021

Procedural recommendations of cardiac PET/CT imaging: standardization in inflammatory-, infective-, infiltrative-, and innervation- (4Is) related cardiovascular diseases: a joint collaboration of the EACVI and the EANM: summary.

Authors:
Riemer H J A Slart Andor W J M Glaudemans Olivier Gheysens Mark Lubberink Tanja Kero Marc R Dweck Gilbert Habib Oliver Gaemperli Antti Saraste Alessia Gimelli Panagiotis Georgoulias Hein J Verberne Jan Bucerius Christoph Rischpler Fabien Hyafil Paola A Erba

Eur Heart J Cardiovasc Imaging 2020 12;21(12):1320-1330

Medical Imaging Centre, Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands.

With this summarized document we share the standard for positron emission tomography (PET)/(diagnostic)computed tomography (CT) imaging procedures in cardiovascular diseases that are inflammatory, infective, infiltrative, or associated with dysfunctional innervation (4Is) as recently published in the European Journal of Nuclear Medicine and Molecular Imaging. This standard should be applied in clinical practice and integrated in clinical (multicentre) trials for optimal standardization of the procedurals and interpretations. A major focus is put on procedures using [18F]-2-fluoro-2-deoxyglucose ([18F]FDG), but 4Is PET radiopharmaceuticals beyond [18F]FDG are also described in this summarized document. Whilst these novel tracers are currently mainly applied in early clinical trials, some multicentre trials are underway and we foresee in the near future their use in clinical care and inclusion in the clinical guidelines. Diagnosis and management of 4Is related cardiovascular diseases are generally complex and often require a multidisciplinary approach by a team of experts. The new standards described herein should be applied when using PET/CT and PET/magnetic resonance, within a multimodality imaging framework both in clinical practice and in clinical trials for 4Is cardiovascular indications.
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http://dx.doi.org/10.1093/ehjci/jeaa299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695243PMC
December 2020

Incorporating Coronary Calcification Into Pre-Test Assessment of the Likelihood of Coronary Artery Disease.

Authors:
Simon Winther Samuel Emil Schmidt Thomas Mayrhofer Hans Erik Bøtker Udo Hoffmann Pamela S Douglas William Wijns Jeroen Bax Louise Nissen Vibeke Lynggaard Jens Juel Christiansen Antti Saraste Morten Bøttcher Juhani Knuuti

J Am Coll Cardiol 2020 11;76(21):2421-2432

Heart Center, Turku University Hospital, Turku, Finland; Turku PET Centre, Turku University Hospital, University of Turku, Turku, Finland.

Background: The prevalence of obstructive coronary artery disease (CAD) in symptomatic patients referred for diagnostic testing has declined, warranting optimization of individualized diagnostic strategies.

Objectives: This study sought to present a simple, clinically applicable tool enabling estimation of the likelihood of obstructive CAD by combining a pre-test probability (PTP) model (Diamond-Forrester approach using sex, age, and symptoms) with clinical risk factors and coronary artery calcium score (CACS).

Methods: The new tool was developed in a cohort of symptomatic patients (n = 41,177) referred for diagnostic testing. The risk factor-weighted clinical likelihood (RF-CL) was calculated through PTP and risk factors, while the CACS-weighted clinical likelihood (CACS-CL) added CACS. The 2 calculation models were validated in European and North American cohorts (n = 15,411) and compared with a recently updated PTP table.

Results: The RF-CL and CACS-CL models predicted the prevalence of obstructive CAD more accurately in the validation cohorts than the PTP model, and markedly increased the area under the receiver-operating characteristic curves of obstructive CAD: for the PTP model, 72 (95% confidence intervals [CI]: 71 to 74); for the RF-CL model, 75 (95% CI: 74 to 76); and for the CACS-CL model, 85 (95% CI: 84 to 86). In total, 38% of the patients in the RF-CL group and 54% in the CACS-CL group were categorized as having a low clinical likelihood of CAD, as compared with 11% with the PTP model.

Conclusions: A simple risk factor and CACS-CL tool enables improved prediction and discrimination of patients with suspected obstructive CAD. The tool empowers reclassification of patients to low likelihood of CAD, who need no further testing.
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http://dx.doi.org/10.1016/j.jacc.2020.09.585DOI Listing
November 2020

Global and segmental absolute stress myocardial blood flow in prediction of cardiac events: [O] water positron emission tomography study.

Authors:
Esa Harjulahti Teemu Maaniitty Wail Nammas Iida Stenström Fausto Biancari Jeroen J Bax Juhani Knuuti Antti Saraste

Eur J Nucl Med Mol Imaging 2021 05 11;48(5):1434-1444. Epub 2020 Nov 11.

Turku PET Centre, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, 20520, Turku, Finland.

Purpose: We evaluated the value of reduced global and segmental absolute stress myocardial blood flow (sMBF) quantified by [O] water positron emission tomography (PET) for predicting cardiac events in patients with suspected obstructive coronary artery disease (CAD).

Methods: Global and segmental sMBF during adenosine stress were retrospectively quantified in 530 symptomatic patients who underwent [O] water PET for evaluation of coronary stenosis detected by coronary computed tomography angiography.

Results: Cardiovascular death, myocardial infarction, or unstable angina occurred in 28 (5.3%) patients at a 4-year follow-up. Reduced global sMBF was associated with events (area under the receiver operating characteristic curve 0.622, 95% confidence interval (95% CI) 0.538-0.707, p = 0.006). Reduced global sMBF (< 2.2 ml/g/min) was found in 22.8%, preserved global sMBF despite segmentally reduced sMBF in 35.3%, and normal sMBF in 41.9% of patients. Compared with normal sMBF, reduced global sMBF was associated with the highest risk of events (adjusted hazard ratio (HR) 6.970, 95% CI 2.271-21.396, p = 0.001), whereas segmentally reduced sMBF combined with preserved global MBF predicted an intermediate risk (adjusted HR 3.251, 95% CI 1.030-10.257, p = 0.044). The addition of global or segmental reduction of sMBF to clinical risk factors improved risk prediction (net reclassification index 0.498, 95% CI 0.118-0.879, p = 0.010, and 0.583, 95% CI 0.203-0.963, p = 0.002, respectively).

Conclusion: In symptomatic patients evaluated for suspected obstructive CAD, reduced global sMBF by [O] water PET identifies those at the highest risk of adverse cardiac events, whereas segmental reduction of sMBF with preserved global sMBF is associated with an intermediate event risk.
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http://dx.doi.org/10.1007/s00259-020-05093-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113164PMC
May 2021

EACVI survey on investigations and imaging modalities in chronic coronary syndromes.

Authors:
Anda Bularga Antti Saraste Ricardo Fontes-Carvalho Espen Holte Matteo Cameli Blazej Michalski Michelle C Williams Tomaz Podlesnikar Antonello D'Andrea Ivan Stankovic Nicholas L Mills Robert Manka David E Newby Jeanette Schultz-Menger Kristina H Haugaa Marc R Dweck

Eur Heart J Cardiovasc Imaging 2021 01;22(1):1-7

BHF Centre for Cardiovascular Science, Department of Cardiology, University of Edinburgh, Edinburgh, EH16 4SB, UK.

Aims: The European Association of Cardiovascular Imaging (EACVI) Scientific Initiatives Committee performed a global survey to evaluate current practice for the assessment and management of patients with suspected and confirmed chronic coronary syndromes.

Methods And Results: One-hundred and ten imaging centres from 37 countries across the world responded to the survey. Most non-invasive investigations for coronary artery disease were widely available, except cardiovascular magnetic resonance (available 40% centres). Coronary computed tomography angiography (CCTA) and nuclear scans were reported by a multi-disciplinary team in only a quarter of centres. In the initial assessment of patients presenting with chest pain, only 32% of respondents indicated that they rely on pre-test probability for selecting the optimal imaging test while 31% proceed directly to CCTA. In patients with established coronary artery disease and recurrent chest pain, respondents opted for stress echocardiography (27%) and nuclear stress perfusion scans (26%). In asymptomatic patients with coronary artery disease and an obstructive (>70%) right coronary artery stenosis, 58% of respondents were happy to pursue medical therapy without further testing or intervention. This proportion fell to 29% with left anterior descending artery stenosis and 1% with left main stem obstruction. In asymptomatic patients with evidence of moderate-to-severe myocardial ischaemia (15%), only 18% of respondents would continue medical therapy without further investigation.

Conclusion: Despite guidelines recommendations pre-test probability is used to assess patients with suspected coronary artery in a minority of centres, one-third of centres moving directly to CCTA. Clinicians remain reticent to pursue a strategy of optimal medical therapy without further investigation or intervention in patients with controlled symptoms but obstructive coronary artery stenoses or myocardial ischaemia.
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http://dx.doi.org/10.1093/ehjci/jeaa300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758034PMC
January 2021

EANM procedural guidelines for PET/CT quantitative myocardial perfusion imaging.

Authors:
Roberto Sciagrà Mark Lubberink Fabien Hyafil Antti Saraste Riemer H J A Slart Denis Agostini Carmela Nappi Panagiotis Georgoulias Jan Bucerius Christoph Rischpler Hein J Verberne

Eur J Nucl Med Mol Imaging 2021 04 2;48(4):1040-1069. Epub 2020 Nov 2.

Department of Radiology and Nuclear Medicine, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The Netherlands.

The use of cardiac PET, and in particular of quantitative myocardial perfusion PET, has been growing during the last years, because scanners are becoming widely available and because several studies have convincingly demonstrated the advantages of this imaging approach. Therefore, there is a need of determining the procedural modalities for performing high-quality studies and obtaining from this demanding technique the most in terms of both measurement reliability and clinical data. Although the field is rapidly evolving, with progresses in hardware and software, and the near perspective of new tracers, the EANM Cardiovascular Committee found it reasonable and useful to expose in an updated text the state of the art of quantitative myocardial perfusion PET, in order to establish an effective use of this modality and to help implementing it on a wider basis. Together with the many steps necessary for the correct execution of quantitative measurements, the importance of a multiparametric approach and of a comprehensive and clinically useful report have been stressed.
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http://dx.doi.org/10.1007/s00259-020-05046-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603916PMC
April 2021

Procedural recommendations of cardiac PET/CT imaging: standardization in inflammatory-, infective-, infiltrative-, and innervation (4Is)-related cardiovascular diseases: a joint collaboration of the EACVI and the EANM.

Authors:
Riemer H J A Slart Andor W J M Glaudemans Olivier Gheysens Mark Lubberink Tanja Kero Marc R Dweck Gilbert Habib Oliver Gaemperli Antti Saraste Alessia Gimelli Panagiotis Georgoulias Hein J Verberne Jan Bucerius Christoph Rischpler Fabien Hyafil Paola A Erba

Eur J Nucl Med Mol Imaging 2021 04 27;48(4):1016-1039. Epub 2020 Oct 27.

Medical Imaging Centre, Department of Nuclear Medicine & Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

With this document, we provide a standard for PET/(diagnostic) CT imaging procedures in cardiovascular diseases that are inflammatory, infective, infiltrative, or associated with dysfunctional innervation (4Is). This standard should be applied in clinical practice and integrated in clinical (multicenter) trials for optimal procedural standardization. A major focus is put on procedures using [F]FDG, but 4Is PET radiopharmaceuticals beyond [F]FDG are also described in this document. Whilst these novel tracers are currently mainly applied in early clinical trials, some multicenter trials are underway and we foresee in the near future their use in clinical care and inclusion in the clinical guidelines. Finally, PET/MR applications in 4Is cardiovascular diseases are also briefly described. Diagnosis and management of 4Is-related cardiovascular diseases are generally complex and often require a multidisciplinary approach by a team of experts. The new standards described herein should be applied when using PET/CT and PET/MR, within a multimodality imaging framework both in clinical practice and in clinical trials for 4Is cardiovascular indications.
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http://dx.doi.org/10.1007/s00259-020-05066-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041672PMC
April 2021

Proteomic Evaluation of the Comorbidity-Inflammation Paradigm in Heart Failure With Preserved Ejection Fraction: Results From the PROMIS-HFpEF Study.

Authors:
Sandra Sanders-van Wijk Jasper Tromp Lauren Beussink-Nelson Camilla Hage Sara Svedlund Antti Saraste Stanley A Swat Cynthia Sanchez Joyce Njoroge Ru-San Tan Maria Lagerström Fermer Li-Ming Gan Lars H Lund Carolyn S P Lam Sanjiv J Shah

Circulation 2020 11 9;142(21):2029-2044. Epub 2020 Oct 9.

Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (S.S.-v.W., L.B.-N., S.A.S., C.S., J.N., S.J.S.).

Background: A systemic proinflammatory state has been hypothesized to mediate the association between comorbidities and abnormal cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). We conducted a proteomic analysis to investigate this paradigm.

Methods: In 228 patients with HFpEF from the multicenter PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction), 248 unique circulating proteins were quantified by a multiplex immunoassay (Olink) and used to recapitulate systemic inflammation. In a deductive approach, we performed principal component analysis to summarize 47 proteins known a priori to be involved in inflammation. In an inductive approach, we performed unbiased weighted coexpression network analyses of all 248 proteins to identify clusters of proteins that overrepresented inflammatory pathways. We defined comorbidity burden as the sum of 8 common HFpEF comorbidities. We used multivariable linear regression and statistical mediation analyses to determine whether and to what extent inflammation mediates the association of comorbidity burden with abnormal cardiac structure/function in HFpEF. We also externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without heart failure.

Results: Comorbidity burden was associated with abnormal cardiac structure/function and with principal components/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e' ratio, and tricuspid regurgitation velocity; and worse right ventricular function (tricuspid annular plane systolic excursion and right ventricular free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19%-35%), E/e' ratio (18%-29%), tricuspid regurgitation velocity (27%-41%), and tricuspid annular plane systolic excursion (13%) (<0.05 for all), but not right ventricular free wall strain. TNFR1 (tumor necrosis factor receptor 1), UPAR (urokinase plasminogen activator receptor), IGFBP7 (insulin-like growth factor binding protein 7), and GDF-15 (growth differentiation factor-15) were the top individual proteins that mediated the relationship between comorbidity burden and echocardiographic parameters. In the validation cohort, inflammation was upregulated in HFpEF cases versus controls, and the most prominent inflammation protein cluster identified in PROMIS-HFpEF was also present in HFpEF cases (but not controls) in the validation cohort.

Conclusions: Proteins involved in inflammation form a conserved network in HFpEF across 2 independent cohorts and may mediate the association between comorbidity burden and echocardiographic indicators of worse hemodynamics and right ventricular dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686082PMC
November 2020

Design and rationale of FLAVOUR: A phase IIa efficacy study of the 5-lipoxygenase activating protein antagonist AZD5718 in patients with recent myocardial infarction.

Authors:
Eva Prescott John Pernow Antti Saraste Axel Åkerblom Oskar Angerås David Erlinge Erik L Grove Marja Hedman Lisette O Jensen Sara Svedlund Magnus Kjaer Maria Lagerström-Fermér Li-Ming Gan

Contemp Clin Trials Commun 2020 Sep 30;19:100629. Epub 2020 Jul 30.

Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, and Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.

Patients with coronary artery disease remain at increased risk of recurrent life-threatening cardiovascular events even after adequate guideline-based treatment of conventional risk factors, including blood lipid levels. Inflammation is a critical pathway in the pathogenesis of atherosclerosis and is independently associated with risk of recurrent cardiovascular events. Leukotrienes are potent pro-inflammatory and vasoactive mediators synthesized by leukocytes in atherosclerotic lesions. AZD5718 is a novel antagonist of 5-lipoxygenase activating protein that suppresses leukotriene biosynthesis. FLAVOUR is a phase IIa efficacy and safety study of AZD5718 in patients with myocardial infarction 1-4 weeks before randomization. Stenosis of the left anterior descending coronary artery after percutaneous intervention must be <50%, and Thrombolysis In Myocardial Infarction flow grade must be ≥ 2. Enrolled participants receive standard care plus oral AZD5718 200 mg, 50 mg, or placebo once daily for up to 12 weeks (extended from 4 weeks by protocol amendment). The planned sample size is 100 participants randomized to 12 weeks' treatment. Change in urine leukotriene E levels is the primary efficacy outcome. FLAVOUR also aims to evaluate whether AZD5718 can improve coronary microvascular function, as measured by transthoracic colour Doppler-assisted coronary flow velocity reserve. Centrally pretrained study sonographers use standardized protocols and equipment. Additional outcomes include assessment of comprehensive echocardiographic parameters (including coronary flow, global strain, early diastolic strain rate and left ventricular ejection fraction), arterial stiffness, biomarkers, health-related quality of life, and safety. Specific anti-inflammatory therapies may represent novel promising treatments to reduce residual risk in patients with coronary artery disease. By combining primary pharmacodynamic and secondary cardiovascular surrogate efficacy outcomes, FLAVOUR aims to investigate the mechanistic basis and potential benefits of AZD5718 treatment in patients with coronary artery disease.
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http://dx.doi.org/10.1016/j.conctc.2020.100629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451793PMC
September 2020

Association of Coronary Microvascular Dysfunction With Heart Failure Hospitalizations and Mortality in Heart Failure With Preserved Ejection Fraction: A Follow-up in the PROMIS-HFpEF Study.

Authors:
Camilla Hage Sara Svedlund Antti Saraste Ulrika Ljung Faxén Lina Benson Maria Lagerstrom Fermer Li-Ming Gan Sanjiv J Shah Carolyn S P Lam Lars H Lund

J Card Fail 2020 Nov 23;26(11):1016-1021. Epub 2020 Aug 23.

Department of Medicine, Cardiology Unit, Karolinska Institutet, Stockholm, Sweden; Karolinska University hospital, Heart, Vascular and Neuro Theme, Karolinska University hospital, Stockholm, Sweden.

Background: Coronary microvascular dysfunction (CMD) is common in heart failure with preserved ejection fraction (HFpEF). We assessed the association of CMD with hospitalization and mortality in HFpEF.

Methods And Results: We assessed the 1-year outcomes in patients from the PROMIS-HFpEF study, a prospective observational study of patients with chronic stable HFpEF undergoing coronary flow reserve measurements. Outcomes were (1) time to cardiovascular (CV) death/first HF hospitalization, (2) CV death/recurrent HF hospitalizations, (3) all-cause death/first HF hospitalization, and (4) first and (5) recurrent all-cause hospitalizations. CMD was defined as coronary flow reserve of <2.5. Time to CV death/first hospitalization was compared by log-rank test and recurrent HF and all-cause hospitalizations by Poisson test. Of 263 patients enrolled, 257 were evaluable at 1 year. Where the coronary flow reserve was interpretable (n = 201), CMD was present in 150 (75%). The median follow-up was 388 days (Q1, Q3 365, 418). The outcome of CV death/first HF hospitalization occurred in 15 patients (4 CV deaths). The incidence rate was in CMD 96 per 1000 person-years, 95% confidence interval 54-159, vs non-CMD 0 per1000 person-years, 95% confidence interval 0-68, P = .023, and remained significant after accounting for selected clinical variables. In patients with CMD, the incidence rates were significantly higher also for CV death/recurrent HF hospitalizations, all-cause death/first HF, and recurrent but not first all-cause hospitalization.

Conclusions: In this exploratory assessment of the prognostic role of CMD in HFpEF, CMD was independently associated with primarily CV- and HF-specific events. The high prevalence of CMD and its CV and HF specific prognostic role suggest CMD may be a potential treatment target in HFpEF.
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http://dx.doi.org/10.1016/j.cardfail.2020.08.010DOI Listing
November 2020
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