bluuebunny/crossref_metadata_2025 huggingface dataset:
AD-9308 ameliorates the impacts of 4-HNE on the progress of pulmonary arterial hypertension in aldehyde dehydrogenase 2*1*2 knock-in mice
Authors: Chou Y H , Lee Y N , Su C H , Yeh H I , Wu Y J
Published: October 2022

Endothelial dysfunctions play a critical role on the development of pulmonary arterial hypertension (PAH). It has been reported that the one-year mortality rate is still up to 15% even with PAH-targeted therapy, implying that there may be untargeted pathways. 4-hydroxynenonal (4-HNE), an unsaturated aldehyde, is highly induced in the lungs of PAH animals and its serum levels were also reported to be higher in PAH patients. 4-HNE is metabolized by mitochondrial aldehyde dehydrogenase (ALDH2), which is dysfunctional in near 40% of East Asian people. Currently, the impacts of 4-HNE on endothelial dysfunctions in the development of PAH are unclear. In terms of translational medicine, we proposed that modulation of 4-HNE level may alleviate the progress of PAH patients with ALDH2 deficiency.

We found that 4-HNE alone was not sufficient to induce pulmonary artery endothelial cell (PAEC) functional changes, including proliferation, migration and tube formation, whereas their effects emerge from the depletion of ALDH2. We further mimicked human ALDH2 functional deficiency by using daidzin (DZN), an inhibitor which is able to block the substrate binding site of ALDH2. ALDH2 functional inhibition alone did not induce any PAEC functional change, while an add-on of 4-HNE impaired PAEC functions. In addition, 4-HNE significantly reduced eNOS activity with combined DZN treatment. Consistent with the mechanism of ALDH2 activity-mediated angiogensis, ALDH2 enhancers Alda-1 and AD-5591 completely reverse the anti-angiogenic effects of 4-HNE in the presence of DZN. To further confirm whether ALDH2 functional deficiency impact on PAH development in mammals, heterozygous ALDH2*1/*2 transgenic and wild-type mice were subjected to chronic hypoxia to induce PAH. ALDH2*1/*2 transgenic mice had similar right ventricular systolic pressure (RVSP) as wild-type mice. However, after exposure to chronic hypoxia, ALDH2*1/*2 transgenic mice indeed developed a significantly higher RVSP than that in wild-type mice. Furthermore, we demonstrated that 4-HNE expression was profoundly enhanced in ALDH2*1/*2 transgenic mice by chronic hypoxia-induced PAH with pulmonary artery smooth muscle cell hyperplasia. More importantly, we found that AD-9308, an enhancer of ALDH2 significantly decreased hypoxia-induced RVSP elevation in heterozygous ALDH2*1/*2 transgenic mice.

Taken together, our data demonstrate that 4-HNE and ALDH2 functional deficiency potentially contribute to PAH development and worsening, and that ALDH2 enhancers may be promising as a PAH adjunct therapy, particularly for patients with ALDH2 nonfunctional alleles.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Science and Technology, Taiwan
Focused ultrasound stimulation of the inflammatory reflex at the spleen ameliorates pulmonary arterial hypertension in rodents
Authors: Zafeiropoulos S , Ahmed U , Giannakoulas G , Puleo C , Zanos S
Published: October 2022

Background

Inflammation is a major contributor in pulmonary arterial hypertension (PAH) pathogenesis. Non-invasive, focused ultrasound stimulation (FUS) of the spleen activates the neuroimmune inflammatory reflex (IR) and suppresses systemic inflammation [1].

Purpose

We aimed to explore whether daily FUS of the spleen improves haemodynamics and biomarkers by modulating the IR, in a rat model of PAH.

Methods

Sprague-Dawley rats (n=12) were injected s.c. with Sugen5416 (VEGF receptor inhibitor) and then, were placed in a hypoxic chamber (FiO2=10%) for 21 days, followed by 14 days of re-exposure to normoxia (FiO2=10%). At day 21, rats were randomized to either FUS (n=6) or sham-stimulation of the spleen (n=6). Each FUS- or sham-stimulation session consisted of 12 minutes. After 14 days of treatment, in a terminal experiment, right ventricular systolic pressure (RVSP) and arterial pressure were measured invasively, as well as biomarkers, in each animal (Figure 1A).

Results

FUS significantly reduced RVSP compared with the sham-stimulation (Mean±SEM, 50.83±3.57 mmHg vs 72.50±5.81; p=0.009), resulting in a 30% relative reduction (Figure 1B). Mean systemic arterial pressure was similar in the 2 groups (Mean±SEM, 79.83±3.73 mmHg vs. 87.00±2.95; p=0.137) (Figure 1C), as was the change in heart rate between day 1 and day 14 of treatment period (−19.53±5.36% vs. −16.79±3.1, p=0.61) (Figure 1D). Consistently, plasma brain natriuretic peptide (BNP) levels are reduced in the FUS group (119.45±19.93 ng/μl vs. 319.39±91.85; p=0.019), indicative of reduced myocardial wall stress in the FUS group (Figure 1E).

Conclusion

Non-invasive FUS of the spleen reduced RVSP by ∼30% and BNP without significantly affecting systemic pressure or heart rate, in rats with severe PAH. Non-invasive FUS, by modulating the IR, may exert an anti-inflammatory effect in PAH. FUS of the spleen is noninvasive, safe, widely available and easy to perform, and should be further explored as a possible therapeutic option in PAH.

Funding Acknowledgement

Type of funding sources: Private hospital(s). Main funding source(s): Northwell Health
Incremental prognostic value of coronary flow reserve derived from SPIM digital positron emission tomography
Authors: Ahmed A I , Saad J M , Alahdab F , Han Y , Alfawara M , Nabi F , Mahmarian J , Al-Mallah M H
Published: October 2022

Introduction

Positron emission tomography (PET) myocardial perfusion imaging (MPI) is an established test in the diagnosis and prognosis of patients with cardiac diseases. Silicon photomultiplier (SiPM) digital PET is the latest advancement in this technology with improved detector sensitivity, coincidence time resolution, and spatial resolution, allowing for Sub-milliSievert cardiac PET MPI.

Purpose

We aimed to assess the independent and incremental prognostic value of SiPM digital PET derived coronary flow reserve (CFR) to clinical and nuclear variables.

Methods

Consecutive patients who had clinically indicated digital Rubidium PET MPI were included. Rubidium dose was 10–20 mCi according to patient's weight. Patients were followed from the date of imaging to incident major adverse cardiovascular event (MACE: inclusive of all-cause death, myocardial infarction, admission for heart failure and late revascularization – percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) >90 days after imaging).

Results

The study population consisted of 2,893 patients with clinically indicated PET MPI (mean age 67 (±12), 53% male, 41% Caucasian). Cardiovascular risk factors were prevalent (88% hypertensive, 80% dyslipidemic, 47% diabetics, 18% ever smoking). After a mean follow-up of 8±7 months, 250 patients (8.6%, 10.7 per 1000 person-year) experienced MACE (90 D / 38 MI / 51 PCI / 11 CABG / 113 HF). In nested multivariable cox models, CFR was independently associated with incident MACE (HR 0.38, 95% CI 0.29–0.51, p<0.001) and incrementally improved risk prediction (Harrell's C=0.77, p=0.002).

Conclusion

Our findings showed that a Sub-milliSievert SiPM digital PET-derived CFR provided incremental value in risk-stratifying patients and identifying those at increased risk of incident outcomes.

Funding Acknowledgement

Type of funding sources: None.
Time-related aortic inflammatory response, as assessed with 18F-FDG PET/CT, in patients hospitalized with severely or critical COVID-19
Authors: Solomou E , Terentes-Printzios D , Gardikioti V , Katsaounou P , Exarchos D , Economou D , Christopoulou G , Kalkinis A D , Kafouris P , Antonopoulos A , Kotanidou A , Datseris I , Tsioufis K , Anagnostopoulos C D , Vlachopoulos C
Published: October 2022

Aim

Arterial involvement has been implicated in the coronavirus disease of 2019 (COVID-19). Fluorine 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging is a valuable tool for the assessment of aortic inflammation and is a predictor of outcome. We sought to prospectively assess the presence of aortic inflammation and its time-dependent trend in patients with COVID-19.

Methods

Between November 2020 and May 2021, in this pilot, case-control study, we recruited 20 patients with severe or critical COVID-19 (mean age of 59±12 years), while 10 age and sex-matched individuals served as the control group. Aortic inflammation was assessed by measuring 18F-FDG uptake in PET/CT performed 20–120 days post-admission. Global aortic target to background ratio (GLA-TBR) was calculated as the sum of TBRs of ascending and descending aorta, aortic arch, and abdominal aorta divided by 4. Index aortic segment TBR (IAS-TBR) was designated as the aortic segment with the highest TBR.

Results

There was no significant difference in aortic 18F-FDG PET/CT uptake between patients and controls (GLA-TBR: 1.46 [1.40–1.57] vs. 1.43 [1.32–1.70], respectively, p=0.422 and IAS-TBR: 1.60 [1.50–1.67] vs. 1.50 [1.42–1.61], respectively, p=0.155). There was a moderate correlation between aortic TBR values (both GLA and IAS) and time distance from admission to 18F-FDG PET-CT scan (Spearman's rho=−0.528, p=0.017 and Spearman's rho=−0.480, p=0.032, respectively), Figure 1. Patients who were scanned less than or equal to 60 days from admission (n=11) had significantly higher GLA-TBR values compared to patients that were examined more than 60 days post-admission (GLA-TBR: 1.53 [1.42–1.60] vs. 1.40 [1.33–1.45], respectively, p=0.016 and IAS-TBR: 1.64 [1.51–1.74] vs. 1.52 [1.46–1.60], respectively, p=0.038). There was a significant difference in IAS-TBR between patients scanned ≤60 days and controls (1.64 [1.51–1.74] vs. 1.50 [1.41–1.61], p=0.036), Figure 2.

Conclusion

This is the first study suggesting that aortic inflammation, as assessed by 18F-FDG PET/CT imaging, is increased in the early post-COVID phase in patients with severe or critical COVID-19 and largely resolves over time. Our findings may have important implications for the understanding of the course of the disease and for improving our preventive and therapeutic strategies.

Funding Acknowledgement

Type of funding sources: None.
Exploring macrophage mannose receptor expression after myocardial infarction by Al[18F]F-NOTA-DCM positron emission tomography
Authors: Andriana P , Lijenback H , Iqbal I , Palani S , Makrypidi K , Virta J , Herre E A , Jalkanen S , Knuuti J , Pirmettis I , Li X G , Saraste A , Roivainen A
Published: October 2022

Introduction

Mannose receptor (CD206) is primarily expressed on the surface of alternatively activated macrophages that are involved in resolution of inflammation after myocardial injury [1]. The purpose of this study was to evaluate mannose receptor targeting positron emission tomography (PET) tracer Al[18F]F-NOTA-DCM consisting of dextran backbone with cysteine-mannose moieties for imaging of experimental acute myocardial infarction (MI) [2].

Methods

First, ALEXA-488 fluorophore-labelled DCM was used for specificity studies using flow cytometry of M1 and M2 polarized macrophages derived from human blood monocytes. Secondly, Sprague-Dawley rats were studied on day 3 and day 7 after permanent ligation of left coronary artery or after sham-operation. [18F]FDG PET (35 MBq, 10 min static scan) was performed to visualize myocardium and on the next day, 60 min dynamic PET was performed after injection of 50 MBq of Al[18F]F-NOTA-DCM. Then, rats were euthanized for biodistribution study by gamma counting followed by digital autoradiography and histology (H&E, CD206 staining) of left ventricle cryosections. In vitro Al[18F]F-NOTA-DCM blocking study was performed on left ventricle cryosection with molar excess of unlabelled DCM.

Results

Flow cytometry confirmed that ALEXA-488-DCM bound specifically to M2 macrophages. In rats, the infarcted area was clearly detected in vivo with Al[18F]F-NOTA-DCM PET and its SUV was significantly higher than that of remote area or myocardium of sham-operated rats both on day 3 (SUV 0.78±0.18 vs. 0.47±0.13 vs. 0.43±0.07, p<0.005) and day 7 post-MI (SUV 0.64±0.10 vs. 0.47±0.12 vs. 0.51±0.07, p<0.05). Autoradiography confirmed increased uptake in the infarcted area compared to the remote area or to the myocardium of sham-operated rats on day 3 (PSL/mm2 141.21±46.06 vs. 49.76±20.37 vs. 57.97±6.77, p<0.005) and day 7 (PSL/mm2 139.22±19.44 vs. 55.38±28.83 vs. 60.83±7.63, p<0.0001). In vitro blocking study indicated that the tracer binding in infarcted area was specific. The area-% of CD206-positive staining in the infarcted area was significantly higher on day 3 post-MI than on day 7 (p<0.05), and higher at both time points than in remote area or myocardium of sham-operated rats (p<0.0001). Area-% of CD206 staining in the MI area positively correlated with Al[18F]F-NOTA-DCM uptake and MI size (p<0.05 and p<0.01, respectively).

Conclusions

Al[18F]F-NOTA-DCM PET detects overexpression of mannose receptor after ischemic myocardial injury and may be a suitable biomarker for early detection of the inflammation resolution process after MI.

Funding Acknowledgement

Type of funding sources: Foundation. Main funding source(s): Jane and Aatos Erkko FoundationSigrid Juselius FoundationFInnish Foundation for Cardiovascular Research
Epicardial adipose tissue in patients with systemic sclerosis
Authors: Wang X , Butcher S , Myagmardorj R , Liem S , Vries-Bouwstra J , Delgado V , Bax J , Marsan N
Published: October 2022

Background

Cardiac involvement is a major cause of death in patients with systemic sclerosis (SSc). Epicardial adipose tissue (EAT) has recently emerged as a mediator between systemic inflammatory disorders and cardiovascular disease, and may therefore play a role in the pathophysiology of cardiac involvement in SSc.

Purpose

To assess the correlation between EAT mass and left ventricular (LV) function, and to determine the prognostic value of EAT in patients with SSc.

Methods

Consecutive patients with SSc who underwent non-contrast thorax computed tomography and echocardiography were included. EAT mass was quantified using dedicated software (Figure A). The study endpoint was all-cause mortality.

Results

A total of 230 SSc patients [age 53±15 years, 14% male] were included. The median value of EAT mass was 67g (IQR: 45–101g). Patients with increased EAT mass (≥67g) showed specifically more impaired LV diastolic function as compared to patients with less EAT mass (<67g). After adjusting for age and comorbidities, EAT remained independently associated with LV diastolic function parameters including left atrial volume index (B=0.031, P=0.025), LV mass index (B=0.139, P=0.036), E/E$'$ (B=0.025, P<0.001) and E' (B=−0.012, P<0.001). During a median follow-up of 8 years 42 patients died, and by Kaplan-Meier analysis patients with increased EAT mass showed higher all-cause mortality rate as compared to patients with less EAT mass (log-rank p<0.001, Figure B). On multivariate analysis, EAT mass was independently associated with all-cause mortality (HR: 1.006; 95% CI: 1.001–1.010; p=0.010).

Conclusion

In patients with SSc, EAT mass is independently associated with LV diastolic dysfunction and higher mortality rate.

Funding Acknowledgement

Type of funding sources: None.
Is cardiac magnetic resonance of additional help in premature ventricular contraction work-up?
Authors: Richard M , Pop A , Hager H , Leven F , Mansourati J
Published: October 2022

Background

Premature ventricular contractions (PVCs) are common in routine medical practice. PVCs are commonly asymptomatic but can also result in palpitations, dyspnea, presyncope or PVC-induced cardiomyopathy that may lead to sudden death. Cardiovascular magnetic resonance (CMR) provides morphological, functional, and tissue characterization in a single setting. CMR imaging proved to reliably identify fibrotic lesions and, hence, has developed into a valuable tool for etiological orientation in patients with PVCs.

Objectives

The aims of this study were: 1) to evaluate which ventricular arrythmia (VA) characteristics predicted CMR abnormalities and 2) the diagnostic yield and the impact in the management of CMR-based imaging versus non-CMR-based imaging in patients referred for PVCs.

Methods

This monocentric retrospective study was conducted in patients with PVCs referred for CMR imaging. Their baseline interview and characteristics, physical examination, surface electrocardiogram (ECG) analysis, ambulatory monitoring, echocardiography and treadmill exercise test data were collected when they were available. The CMR (1,5 T and 3.0 T) protocol included cine imaging and late gadolinium enhancement (LGE) using standard cardiac geometries.

Results

We analyzed 168 patients (65% males, mean age 54.2±16.8 years) referred to our center for PVCs over a two-year period. CMR reported abnormal findings in 73 patients (43.5%) with the diagnosis of structural heart disease (SHD) in 46 patients (27.4%). Left-ventricular late gadolinium-enhancement was documented in 43 patients with abnormal CMR. Using a multivariate analysis, age (p=0.026), sustained ventricular tachycardia (p=0.002) and presence of cardiomyopathy on echocardiography (p<0.001) significantly predicted the presence of abnormal findings on CMR. Compared to non-CMR-based imaging, CMR had a diagnostic yield, by modifying the presumed diagnosis or by finding abnormalities requiring follow-up in 73 patients (43.5%).

Conclusions

Age, sustained ventricular tachycardia and presence of cardiomyopathy on echocardiography were the strongest predictors of positive CMR imaging results. Although echocardiography is generally used in first intention for the diagnosis of cardiomyopathy in patients with PVCs, this study showed that CMR-based imaging has a robust diagnostic yield in this indication.

Funding Acknowledgement

Type of funding sources: None.
Long-standing persistent atrial fibrillation with low coronary flow reserve is associated with unnecessary coronary angiography
Authors: Daniels F , Elvan A , Beemsterboer I T A , Mouden M
Published: October 2022

Background/Introduction

Atrial fibrillation (AF) is associated with an increased risk of myocardial infarction. Myocardial perfusion imaging (MPI) is well-established for the diagnosis of coronary artery disease (CAD) and risk-stratification in sinus rhythm (SR) patients.

Purpose

The aim of this study was to determine the impact of AF and coronary flow reserve (CFR) on revascularization in patients undergoing positron emission tomography (PET) MPI.

Methods

680 patients without a known history of CAD were included. 226 paroxysmal AF (PAF) and 114 long-standing persistent AF (LSPAF) patients were identified from a single-center prospective PET MPI registry and propensity matched in a 1:1 ratio to SR patients. The main indications for PET MPI were chest pain and dyspnea. Follow-up was obtained for downstream referral for invasive coronary angiography (CAG) and the occurrence of myocardial infarction (MI) or coronary revascularization.

Results

Compared with PAF, LSPAF patients were older (p=0.011) and more frequently male (p=0.031), with no significant differences in prior medical history and cardiac risk factors. The number of abnormal scans (infarction or ischemia) did not differ significantly between SR and AF, respectively 22.1% and 18.5% (p=0.253). The frequency of downstream CAG was comparable between the groups (p=0.298), with a significantly higher yield of obstructive CAD in the SR group as compared to PAF and LSPAF groups (63% vs 42% vs 36%, p=0.007). A low CFR (defined as CFR below the median of 2.4) in patients with SR showed significantly more revascularization compared with PAF and LSPAF (p<0.001), although more patients with LSPAF and low CFR underwent CAG (p<0.001). In patients with low CFR referred for CAG, the overall prevalence of obstructive coronary artery disease on CAG was 62%, with 30% for LSPAF, 52% for PAF and 78% for SR. There were no significant differences between SR, PAF and LSPAF in the occurrence of MI during a mean follow-up of 36 months (p=0.256).

Conclusion

A low CFR was only associated with a higher incidence of revascularization in patients with SR. Among patients with low CFR, LSPAF patients have the highest number of unnecessary CAGs as compared with SR and PAF.

Funding Acknowledgement

Type of funding sources: None.
Can echocardiography facilitate decision-making to CRT?
Authors: Puvrez A , Mirea O , Duchenne J , Beela A , Donal E , Voigt J U
Published: October 2022

Introduction

Cardiac resynchronization therapy (CRT) remains underused despite its well-established therapeutic effect and clear guidelines. Among various reasons are the lack of referral, the fear of complications and the high therapy cost. The assessment of mechanical dyssynchrony (MD) on echocardiography has been suggested to aid patient selection. In the past, however, several studies have used old markers of MD producing disappointing results and the use of echocardiography for patient selection became discredited. Promising new markers have been developed since and could aid clinical decision-making for CRT. These should, however, first be thoroughly tested and compared to the old markers.

Purpose

(I) To confirm the relevance of the new markers of MD for survival free of cardiac death and (II) to compare old and new markers of MD for predicting cardiac death within 5 years post-CRT in patients eligible for CRT according the 2021 ESC guidelines.

Methods

222 CRT-patients were analysed retrospectively in a multicentre setting. MD was assessed using three old markers: septal-to-posterior wall-motion-delay (SPWMD), left-ventricular-filling-time/cardiac-cycle ratio (LVFT/RR), and intraventricular mechanical delay (IVMD); and three new markers: systolic stretch index (SSI), myocardial work index (MWI), and visual presence of septal flash or apical rocking (SFoAR). For each marker, patients were categorized using previously published cut-offs as “MD present” (Yes) or “MD not present” (No). Log rank tests were performed on Kaplan-Meier curves for survival free of cardiac death. Cox proportional hazards regressions were used to compute the hazard-ratio (HR) for cardiac death within 5 years after implantation.

Results

Cardiac death occurred in 37 patients (17%). Patients with MD before CRT according to IVMD (p=0.003), SSI (p<0.001), MWI (p<0.001) or SFoAR (p<0.001) had a significantly better survival. The hazard ratios were 0.34 (95% CI, 0.19–0.75) for IVMD, 0.30 (95% CI, 0.15–0.57) for SSI, 0.26 (95% CI, 0.12–0.54) for MWI and, 0.28 (95% CI, 0.14–0.53) for SFoAR. The other markers for MD were not significant for survival.

Conclusion

The new markers for dyssynchrony are better than the old. Patients with mechanical dyssynchrony on echocardiography before CRT according to SSI, MWI or SFoAR are 3 to 4 times less likely to die within 5 years after CRT implantation. The presence of one of these markers in patients with a broad QRS (≥130ms) and reduced LVEF (≤35%) should prompt clinicians to refer for or to proceed to CRT.

Funding Acknowledgement

Type of funding sources: None.
Pericoronary adipose tissue attenuation index (FAI) and its cardiovascular diagnostic and prognostic utility: a systematic review and meta-analysis
Authors: Sagris M , Antonopoulos A S A , Simantiris S S , Oikonomou E O , Siasos G S , Tsioufis K T , Tousoulis D T
Published: October 2022

Background

Pericoronary fat attenuation index (FAI) on coronary computed tomography angiography (CCTA) imaging has been proposed as a novel marker of coronary vascular inflammation with prognostic value for major cardiovascular events. To date though there is no systematic review of the published literature and no meta-analyzed data of previously published results.

Methods

We performed a systematic review and meta-analysis according to the PRISMA guidelines. We systematically explored published literature in MEDLINE (PubMed) before January 20, 2022 for studies assessing FAI in both diagnostic and prognostic clinical settings in patients with or without cardiovascular disease. The primary outcome was the mean difference in FAI attenuation between stable and unstable coronary plaques. The secondary outcome was the hazard ratio of high FAI values for future cardiovascular events. We calculated I2 to test heterogeneity. We used random-effects modelling for the meta-analyses to assess the primary and secondary outcomes. This study is registered with PROSPERO (CRD42021229491).

Results

In total, 20 studies referred in a total of 7,797 patients were included in this systematic review while 9 studies were used for the meta-analysis. FAI was significantly higher in unstable compared to stable plaques with a mean difference of 4.50 HU (95% CI: 1.10–7.89, I2=88%) among 902 patients. Higher pericoronary FAI values offered incremental prognostic value for major adverse cardiovascular events in studies with prospective follow-up (HR=3.29, 95% CI: 1.88–5.76, I2=75%) among 6,335 patients.

Conclusion

FAI is a promising imaging biomarker that may be successfully be used for detection of coronary inflammation, discrimination between stable and unstable plaques, and prognosis of future major adverse cardiovascular events. There is an undeniable need for further studies to establish the utility of this biomarker in clinical practice to improve coronary plaque discrimination and cardiovascular risk prognostication.

Funding Acknowledgement

Type of funding sources: None.
Effect of an optimized X-ray blanket design on operator radiation dose in cardiac catheterization based on real-world angiography
Authors: Davidsen C , Bolstad K , Ytre-Hauge K , Samnoey A , Vikenes K , Tuseth V
Published: October 2022

Background

There is increasing concern and focus in the interventional cardiology community on potential long term health issues related to radiation exposure and heavy wearable protection. Optimized shielding measures may reduce operator dose to levels where lighter radioprotective garments can safely be used, or even omitted. X-ray blankets (XRB) are commercially available but suffer from small size and lack of stability.

Purpose

The aim of this study is to assess shielding effect of an optimized XRB during cardiac catheterization and estimate the potential reduction in annual operator dose based on DICOM Radiation Dose Structured Report (RDSR) data reflecting everyday clinical practice.

Methods

Data accumulated from 7681 procedures over three years in our RDSR repository was used to identify projection angles and radiation doses during cardiac catheterization. Using an anthropomorphic phantom and a scatter radiation detector, radiation dose to the operator (mSv) and patient (dose area product – DAP) was measured for each angiographic projection for three different shielding setups. Relative operator dose (mSv/DAP) was calculated and multiplied by DAP per projection to estimate effect on operator dose.

Results

Adding an optimized XRB to a standard shielding setup comprising a table- and ceiling-mounted shield resulted in a 94.9% reduction in estimated operator dose. The largest shielding effect was observed in left and cranial projections where the ceiling-mounted shield offered less protection.

Conclusions

An optimized XRB is a simple shielding measure that has the potential to reduce operator dose.

Funding Acknowledgement

Type of funding sources: Foundation. Main funding source(s): Grieg Foundation
Relationship between OCT-derived plaque characteristics, CTA-derived coronary inflammation, and CMR-derived global coronary flow reserve in patients with acute coronary syndrome
Authors: Sugiyama T , Kanaji Y , Hoshino M , Hada M , Misawa T , Nagamine T , Ueno H , Matsuda K , Sayama K , Yonetsu T , Sasano T , Kakuta T
Published: October 2022

Background

The presence of layered plaque is suggestive of recurrent thrombotic events. However, the impact of layered plaque detected by optical coherence tomography (OCT) on coronary inflammation and coronary flow reserve remains unclear.

Purpose

We aimed to investigate the association of OCT-derived layered plaque with pericoronary adipose tissue inflammation assessed by coronary computed tomography angiography (cCTA) and global coronary flow reserve (G-CFR) assessed by cardiac magnetic resonance imaging (CMR) in patients with acute coronary syndrome (ACS).

Methods

We investigated 88 patients with first ACS who underwent preprocedural cCTA and OCT imaging of the culprit lesion, and CMR after percutaneous coronary intervention (PCI). All patients were divided into four groups according to the OCT-derived culprit plaque characteristics: layered vs. non-layered plaque; and plaque rupture vs. plaque erosion. Coronary inflammation was assessed by the mean value of pericoronary adipose tissue (PCAT) attenuation (−190 to −30 HU) of the three major coronary vessels. G-CFR was obtained by quantifying absolute coronary sinus flow at rest and during maximum hyperemia. CCTA and CMR findings were compared between the groups.

Results

In a total of 88 patients, layered plaque [L] with plaque rupture [PR] was observed in 25 patients, layered plaque with plaque erosion [PE] was observed in 26 patients, non-layered plaque [NL] with PR was observed in 23 patients, and non-layered plaque with PE was observed in 14 patients, respectively. Three-vessel-PCAT attenuation value (L-PR vs. L-PE vs. NL-PR vs. NL-PE; −68.13±6.18 vs. −69.01±6.72 vs. −69.76±4.04 vs. −74.61±5.63 HU, P=0.009) and culprit vessel PCAT attenuation value (L-PR vs. L-PE vs. NL-PR vs. NL-PE; −66.39±7.38 vs. −68.94±8.06 vs. −70.01±5.76 vs. −75.45±6.60 HU, P=0.003) showed the graded difference between the four groups. G-CFR value also showed the graded difference between the four groups (L-PR vs. L-PE vs. NL-PR vs. NL-PE; 2.26 [1.80–2.87] vs. 2.24 [1.72–3.13] vs. 2.97 [2.24–3.83] vs. 3.18 [2.67–4.08], P=0.022).

Conclusions

The presence of layered plaque at the culprit lesion was associated with high PCATA and low G-CFR in patients with ACS. Detection of layered plaque may indicate increased pericoronary inflammation and impaired coronary flow reserve, potentially providing the risk stratification in patients with ACS.

Funding Acknowledgement

Type of funding sources: None.
A novel clinical and cardiac magnetic resonance risk score for early risk prediction after ST-segment elevation myocardial infarction
Authors: Marcos Garces V , Perez N , Gavara J , Lopez-Lereu M P , Monmeneu J V , Rios-Navarro C , De Dios E , Merenciano-Gonzalez H , Gabaldon-Perez A , Chorro F J , Valente F , Lorenzatti D , Ortiz-Perez J T , Rodriguez-Palomares J F , Bodi V
Published: October 2022

Background

Cardiac magnetic resonance (CMR) performed early after ST-segment elevation myocardial infarction (STEMI) can improve major adverse cardiac event (MACE) risk prediction. However, predictive models including clinical and CMR variables are scarce and not routinely implemented in clinical practice.

Purpose

We aimed to create a simple clinical-CMR risk score for early MACE risk stratification in STEMI patients.

Methods

We performed a multicenter prospective registry in three Spanish university hospitals of reperfused STEMI patients (n=1118) in whom early (1-week) CMR-derived left ventricular ejection fraction (LVEF), infarct size and microvascular obstruction (MVO) were quantified. MACE was defined as a combined clinical endpoint of cardiovascular (CV) death, non-fatal myocardial infarction (NF-MI) or re-admission for acute decompensated heart failure (HF), whichever occurred first. Univariate and multivariate analyses were performed and a risk score was computed using the variables which independently predicted the risk of MACE.

Results

During a median follow-up of 5.52 [2.63–7.44] years, 216 first MACE (58 CV deaths, 71 NF-MI and 87 HF) were registered. Mean age was 59.3±12.3 years and most patients (82.8%) were male. Based on the four variables independently associated with MACE, we computed an 8-point risk score: time to reperfusion >4.15h (1 point), GRACE risk score >155 (3 points), CMR-LVEF <40% (3 points), and MVO >1.5 segments (1 point). This score permitted MACE risk stratification: MACE per 100 person-years was 1.96 in the low-risk category (0–2 points), 5.44 in the intermediate-risk category (3–5 points), and 19.7 in the high-risk category (6–8 points): p<0.001 in multivariable Cox survival analysis.

Conclusions

A novel risk score including clinical (time to reperfusion >4.15h and GRACE risk score >155) and CMR (LVEF <40% and MVO >1.5 segments) variables allows for simple and straightforward MACE risk stratification early after STEMI. External validation should confirm the applicability of the risk score.

Funding Acknowledgement

Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER) and Sociedad Española de Cardiología.
Pulmonary vein anatomical variants and incidence of atrial fibrillation
Authors: Gallen R , Apolinario M , Arsanjani R , Panse P , Jokerst C , Sorajja D
Published: October 2022

Introduction

Atrial fibrillation (AF) is the most common arrhythmia worldwide. The role of the pulmonary veins (PV) in its' pathogenesis has been well described, as have the most frequently seen anatomical variants of these veins. Prior studies have shown conflicting evidence on the potential association of PV variants and incidence of AF. We sought to reassess this association.

Methods

We conducted a retrospective case-control study of patients with AF (cases) and without AF (control group) undergoing cardiac CT imaging. We documented patient characteristics and cardiac anatomical features including PV variants, LV ejection fraction (EF) and left atrial (LA) volume/diameter.

Results

295 patients were included: 194 with AF and 101 without. 71% of AF cases were male. We showed a numerical difference for PV variants between the AF and control group that was not statistically significant (48.5% and 39.6%, p=0.15). The overall incidence of PV variants was higher than in previous studies. A significant association was identified between left atrial appendage (LAA) morphology and incidence of AF.

Conclusion

The suggested association between PV anatomical variants and the pathogenesis of AF may not be as clear-cut as previously thought. Our study is one of the largest of its kind and provides conflicting evidence with prior studies in this area. An improved understanding of the complex pathophysiology of AF and its relation to the pulmonary veins may help to guide future preventative and therapeutic strategies.

Funding Acknowledgement

Type of funding sources: None.
Effects of doxorubicin and ibrutinib on atrial arrhythmogenity: ex-vivo assessment in human myocardium
Authors: Berger Y , Primessnig U , Huettemeister J , Parwani A S , Boldt L H , Pieske B , Falk V , Grubitzsch H , Blaschke F , Heinzel F R
Published: October 2022

Introduction

The cytostatic drugs doxorubicin (Dox) and ibrutinib (Ibr) are established in the treatment of various tumor diseases. In (pre-) clinical studies, both chemotherapeutic agents showed cardiotoxic side effects, including atrial fibrillation [1]. In this context, patients with limited cardiac performance or diabetes might be particularly vulnerable, as these pre-existing conditions represent independent risk factors for cardiac complications [2].

Objectives

The dose-dependency of acute pro-arrhythmogenic effects of Dox and Ibr on the contractile activity of human atrial muscle tissue was investigated.

Patients and methods

Atrial samples were taken intraoperatively during cardiac procedures. Functional muscle strips were prepared from the cardiac trabeculae, followed by incubation with different concentrations of Dox or Ibr for 30 minutes. Subsequently, functional measurements were performed. Isometric contraction force and arrhythmogenic occurrences were recorded. The samples were consecutively exposed to external stressors during measurement (Fig. 1).

We evaluated the overall occurrence of arrhythmogenic contractions and during which phase of the protocol they occurred. The latter was expressed as degree of arrhythmogenesis (Fig. 1).

Following the functional measurements, the muscle strips were conserved at −80°C.

Results

We isolated 127 muscle strips from 29 patients. Highest rates of overall arrhythmic contractions were observed at 10μM Dox and 0.5μM Ibr (77.8 & 100% vs. 58.4% (control)). Mean degree of arrhythmogenesis increased from 1.63 (control) to 2.17 (10μM Dox) and 3.11 (0.5μM Ibr).

Analyzing our data according to the included individuals, treatment with Dox and Ibr enhanced the degree of arrhythmogenesis in the majority of patients. (Fig. 2)

Conclusion

Our protocol is suitable for investigating drug related acute pro-arrhythmogenic effects on human atrial myocardium. Treatment of isolated atrial myocardium with Dox and Ibr enhanced its susceptibility to arrhythmogenic occurrences. Optimal pro-arrhythmogenic conditions were observed at 10μM Dox and 0.5μM Ibr. The treated samples showed higher overall rates of arrhythmogenic contractions and the arrhythmogenic activity occurred earlier within our protocol.

Outlook

We will correlate the experimentally obtained data with clinical patient data, such as LVEF, BMI and diabetic status. The conserved muscle strips will be analyzed using standardized assays comparing post-translational modification (e.g. phosphorylation and oxidation) of key regulators of excitation contraction coupling (e.g. PKA, CaMKII, Ca2+ channels).

Funding Acknowledgement

Type of funding sources: Other. Main funding source(s): DZHK (German Centre for Cardiovascular Research), partner site Berlin
Dapagliflozin exhibits class I antiarrhythmic effects which suppress action potential formation in human atrial cardiomyocytes
Authors: Paasche A , Wiedmann F , Javorszky N , Yesilgoez B , Blochberger P , Kraft M , Frey N , Schmidt C
Published: October 2022

Background

Recently, inhibitors of sodium-glucose transporter 2 (SGLT2i) were shown to have tremendous cardioprotective effects in patients with type 2 diabetes mellitus (T2DM) as well as heart failure (HF) patients, regardless of their glycemic status. Among other beneficial effects on cardiovascular outcome an antiarrhythmic effect of SGLT2i was indicated. In patients with T2DM therapy with SGLT2i was associated with a significantly reduced risk of atrial arrhythmias and sudden cardiac death. As sodium-glucose transporter 2 (SGLT2) is not expressed within the heart underlying molecular modes of action remain unclear. Therefore, investigating possible antiarrhythmic mechanisms is crucial to determine whether SGLT2i might be beneficial for all patients suffering from arrhythmias, regardless of other comorbidities.

Purpose

To assess antiarrhythmic effects of SGLT2i on a molecular and cellular level. Therefore, direct electrophysiological effects of dapagliflozin – the most advanced SGLT2i in clinical trials – on action potential (AP) formation in atrial cardiomyocytes (CM) was investigated.

Methods

Effects of dapagliflozin on human NaV1.5, heterologously expressed in Chinese hamster ovary (CHO) cells, was investigated using the patch-clamp method. Further, effects on voltage-gated sodium channels (NaV) were also measured in human atrial CM. Consequences of dapagliflozin treatment on AP formation were studied on isolated human and porcine atrial CM using the patch-clamp technique. APs were elicited in current-clamp mode by injection of brief current pulses.

Results

Dapagliflozin (100 μM) significantly decreased peak sodium currents in human atrial CM as well as CHO cells, expressing human NaV1.5 channel subunits. Additionally, half-activation potential of voltage-gated sodium channels was significantly increased after administration of dapagliflozin. Furthermore, dapagliflozin (100 μM) suppressed AP formation in CM isolated from human and porcine left and right atrial tissue. In human CM action potential amplitude (APA) was significantly reduced by 34.3%, while APA inhibition by dapagliflozin averaged out at 30.7% for porcine CM. In porcine CM action potential duration at 50% (APD50) and 90% repolarization (APD90) were also significantly reduced.

Conclusion

Dapagliflozin suppresses AP formation in human and porcine atrial CM by inhibiting voltage-gated sodium currents. Therefore, we suppose that dapagliflozin exhibits class I antiarrhythmic effects.

Funding Acknowledgement

Type of funding sources: None.
“Concealed cardiomyopathy” is an important cause of autopsy-inconclusive sudden cardiac death and diagnosis impacts care of surviving relatives
Authors: Isbister J C , Nowak N , Yeates L , Singer E S , Sy R W , Ingles J , Raju H , Bagnall R , Semsarian C
Published: October 2022

Background

Genetic testing following sudden cardiac death (SCD) is currently guided by autopsy findings, despite the inherent challenges of autopsy examination and mounting evidence that malignant arrhythmia may occur prior to structural changes in inherited cardiomyopathy, so-called “concealed cardiomyopathy” (CCM).

Purpose

To identify the spectrum of genes implicated in autopsy-inconclusive SCD and describe the importance of identifying CCM for the ongoing care of SCD families.

Methods

Using a standardised framework for adjudication, autopsy-inconclusive SCD cases were identified as having a structurally normal heart or sub-diagnostic findings of uncertain significance on autopsy. Genetic variants were classified for pathogenicity using the American College of Medical Genetics and Genomics guidelines. Family follow-up was performed where possible.

Results

Twenty disease-causing variants were identified among 91 autopsy-inconclusive SCD cases (mean age 25.4±10.7 years) with a similar rate regardless of the presence or absence of sub-diagnostic findings (25.5% vs 18.2%, p=0.40). Cardiomyopathy-associated genes harboured 70% of clinically-actionable variants and were overrepresented in cases with sub-diagnostic structural changes at autopsy, accounting for 11 out of 12 disease-causing variants in this group (79% vs 21%, p=0.038, Figure 1, panel A). Variants in arrhythmogenic cardiomyopathy genes were the most common cause of CCM (9/14 CCM cases, Figure 1, panel B). Nearly two-thirds of genotype-positive relatives had an observable phenotype either on initial assessment or during subsequent follow-up. Twenty-seven genotype-negative first-degree relatives were released from ongoing screening.

Conclusion

The current paradigm of phenotype-directed genetic testing following SCD risks under recognition of CCM. Comprehensive evaluation of the decedent should include assessment of genes implicated in both cardiomyopathy and primary arrhythmias to improve diagnosis of CCM and optimise care for families.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Heart Foundation of Australia and National Health and Medical Research CouncilNew South Wales Health
Reinterpretation of variant of unknown significance in the clinical setting of inherited cardiac conditions
Authors: Novelli V , Manzoni M , Sommariva E , Colombo G , Biondi M L , Mushtaq S , Farina S , Roberto M , Pizzamiglio F , Casella M , Pompilio G
Published: October 2022

Introduction

In the last years, genetic testing for inherited cardiac conditions (ICCs) is expanded and evolved at an incredible rate. This tool may inform treatment options and lifestyle choices to avoid arrhythmia triggers. Furthermore, identifying the genetic underpinning of the disorder improves risk assessment for asymptomatic or pre-symptomatic family members.

However, despite the large numbers of disease-causative genes identified in the last years, only 60% of the patients with a clinical diagnosis of ICCs carry a pathogenic or likely pathogenic variant. The remaining 40% of the cases have an inconclusive or ambiguous test caused by negative results or mainly by the identification of one or more variants of unknown significance (VUS). In this case, the test results are uninformative and clinically irrelevant, increasing uncertainty about medical management.

Purpose

We investigated whether a periodic re-evaluation of the detected VUS, using the American College of Medical Genetics and Genomics (ACMG) criteria, may impact the clinical setting of patients with suspected ICC and their family members.

Methods

We reevaluated 306 consecutive probands with suspected ICC undergoing genetic testing by next-generation sequencing using the Illumina TruSight Cardio Sequencing panel, from 2017 to 2021.

Results

Thirty-five percent of patients carried at least one variant in a gene associated with the phenotype. Of these, 94 had been previously classified as VUS and were not considered clinically actionable. After an average time of 36 months, they were reevaluated and 26.6% of the VUS were reclassified. In particular, 1 was downgraded to Benign and 24 were upgraded to Likely Pathogenic (16) or Pathogenic (8). According to the different phenotypes, the reclassification rate was 45.8% in Hypertrophic cardiomyopathy, 33.3% in Dilated cardiomyopathy, 27.3% in Arrhythmogenic cardiomyopathy, 12.5% in Brugada syndrome, and 50% in Long QT syndrome patients. This reclassification process allowed to recategorize 24 probands as clinically and molecularly diagnosed and to extend the genetic screening to their at-risk family members.

Conclusions

Given the extent of the clinical impact that genetic testing can have, these findings suggest that a periodic reevaluation of genetic test results, particularly VUS, should be a mandatory step in the ICC diagnostic workflow.

Funding Acknowledgement

Type of funding sources: None.
Characteristics and prognosis of the catecholamine induced QT prolongation syndrome
Authors: Gourraud J , Le Diffon T , Mansourati J , Clementy N , Thollet A , Rajalu A , Cotard V , Kyndt F , Martins R , Sacher F , Probst V
Published: October 2022

Background

We have recently demonstrated association of unexplained sudden cardiac arrest (SCA) with inheritance of catecholamine induced QT prolongation (CIQTP).

Objective

We here aim to describe incidence, characteristics and prognosis of this new syndrome in young patients with unexplained SCA or their relatives.

Methods

We reviewed the medical screening of all consecutive patients or their first-degree relatives explore from 2015 after the occurrence of a SCA before age 45. Structural heart disease or inherited arrhythmia diseases were excluded. A mental stress test was performed, as previously described, for each family members. All families with a positive mental stress were included in the study. Genetic screening was performed in at least one positive patient per family using targeted sequencing on a panel of 109 genes associated with inherited arrhythmias and cardiomyopathies.

Results

Among 456 patients screened (24 after SCA, 432 for familial screening) of 153 families, we identified 10 families (6.5%) with a catecholamine induced QT prolongation. No mutation was identified in these families. One hundred and ten patients were screened in CIQTP families. Thirty-four patients (30.9%) presented a CIQTP (mean age 42±20 yo, 64.7% of women). Five (14.7%) patients presented with previous symptoms (including 4 syncope and 1 SCA).

Two patients (5.9%) were implanted with an ICD and eleven (32.3%) were treated with beta blocker therapy mainly because of QT prolongation >500 ms after mental stress test or previous symptoms.

After a 3.6±1.8 years of follow up, no sudden cardiac death nor syncope occurred on beta blocker therapy except for one patient implanted with an ICD after a SCA. Under beta blocker treatment the patient was asymptomatic for 5 years. After a suddenly stop of the beta blocker treatment, the patient underwent VF. For 3 years now the patient is asymptomatic under beta blocker treatment.

Conclusions

In our experience, CIQTP families represent 6.5% of cases of unexplained SCD and suggest systematic screening with a mental stress test for family screening after the occurrence of a SCA. Beta blocker therapy is very efficient to reduce the risk of SCA.

Funding Acknowledgement

Type of funding sources: None.