Coronary CT Angiography-based Morphologic Index for Predicting Hemodynamically Significant Coronary Stenosis.

Purpose To develop a new coronary CT angiography (CCTA)-based index, α×LL/MLD4, that considers lesion entrance angle (α) in addition to lesion length (LL) and minimal lumen diameter (MLD) and to evaluate its efficacy in predicting hemodynamically significant coronary stenosis compared with invasive coronary angiography (ICA)-derived fractional flow reserve (FFR). Materials and Methods This prospective study enrolled participants (September 2016-March 2020) from two centers who underwent CCTA followed by ICA (ClinicalTrials.gov identifier: NCT03054324). CCTA images were processed semiautomatically to measure LL, MLD, and α for calculating α×LL/MLD4. Diagnostic performance and accuracy of α×LL/MLD4 and LL/MLD4 in detecting hemodynamically significant coronary stenosis were compared against the reference standard (invasive FFR ≤ 0.80). Results In total, 133 participants (mean age, 63 years ± 9 [SD]; 99 [74%] men) with 210 stenosed coronary arteries were analyzed. Median α×LL/MLD4 was 54.0 degree/mm3 (IQR, 25.3-128.7) in participants with invasive FFR of 0.80 or less and 6.7 degree/mm3 (IQR, 3.3-12.8) in participants with invasive FFR of more than 0.80 (P < .001). The per-vessel accuracy, sensitivity, specificity, positive predictive value, and negative predictive value for discriminating ischemic lesions were 86.2%, 83.1%, 88.4%, 84.1%, and 87.7% for α×LL/MLD4 and 80.5%, 66.3%, 90.9%, 84.3%, and 78.6% for LL/MLD4, respectively. Area under the receiver operating characteristic curve for discriminating hemodynamically significant stenosis was 0.93 for α×LL/MLD4, which was significantly greater than the values of 0.84 for LL/MLD4 and 0.63 for diameter stenosis (both P < .001). Conclusion The new morphologic index, α×LL/MLD4, incorporating lesion entrance angle achieved higher diagnostic performance in detecting hemodynamically significant lesions compared with diameter stenosis and LL/MLD4. Keywords: CT Angiography, Cardiac, Coronary Arteries, Ischemia, Infarction, Technology Assessment Clinical trial registration no. NCT03054324 Supplemental material is available for this article. © RSNA, 2023 See also the commentary by Fairbairn and Nørgaard in this issue.

Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease.

BACKGROUND AND AIMS: Single nucleotide polymorphism rs6903956 has been identified as one of the genetic risk factors for coronary artery disease (CAD). However, rs6903956 lies in a non-coding locus on chromosome 6p24.1. We aim to interrogate the molecular basis of 6p24.1 containing rs6903956 risk alleles in endothelial disease biology. METHODS AND RESULTS: We generated induced pluripotent stem cells (iPSCs) from CAD patients (AA risk genotype at rs6903956) and non-CAD subjects (GG non-risk genotype at rs6903956). CRISPR-Cas9-based deletions (Δ63-89bp) on 6p24.1, including both rs6903956 and a short tandem repeat variant rs140361069 in linkage disequilibrium, were performed to generate isogenic iPSC-derived endothelial cells. Edited CAD endothelial cells, with removal of 'A' risk alleles, exhibited a global transcriptional downregulation of pathways relating to abnormal vascular physiology and activated endothelial processes. A CXC chemokine ligand on chromosome 10q11.21, CXCL12, was uncovered as a potential effector gene in CAD endothelial cells. Underlying this effect was the preferential inter-chromosomal interaction of 6p24.1 risk locus to a weak promoter of CXCL12, confirmed by chromatin conformation capture assays on our iPSC-derived endothelial cells. Functionally, risk genotypes AA/AG at rs6903956 were associated significantly with elevated levels of circulating damaged endothelial cells in CAD patients. Circulating endothelial cells isolated from patients with risk genotypes AA/AG were also found to have 10 folds higher CXCL12 transcript copies/cell than those with non-risk genotype GG. CONCLUSIONS: Our study reveals the trans-acting impact of 6p24.1 with another CAD locus on 10q11.21 and is associated with intensified endothelial injury.

Long-term outcomes in acute coronary syndrome patients without standard modifiable risk factors: a multi-ethnic retrospective cohort study Of 5400 asian patients.

A sizeable number of patients without standard modifiable cardiovascular risk factors (SMuRFs), such as hypertension, diabetes, hypercholesterolemia and smoking, suffer from acute coronary syndrome (ACS). These SMuRF-less patients have high short-term morbidity and mortality. We compared both short- and long-term outcomes of SMuRF-less and SMuRF ACS patients in a multi-ethnic Asian cohort.This was a retrospective study of patients with first ACS from 2011 to 2017. The primary outcome was long-term all-cause mortality. Secondary outcomes were 30-day all-cause mortality, cardiac-mortality, unplanned cardiac readmission, cardiogenic shock, heart failure, and stroke. Subgroup analysis was carried out by sex and ACS type.Of 5400 patients, 8.6% were SMuRF-less. The median follow-up time was 6.3 years (interquartile range [IQR] 4.2-8.2 years). SMuRF-less patients were younger and tended to present with ST-segment elevation myocardial infarction (STEMI). They were more likely to require inotropic support, intubation, and have cardiac arrest. At 30 days, SMuRF-less patients had higher rates of all-cause mortality, cardiac-related mortality and cardiogenic shock, but lower rates of heart failure. At 6 years, all-cause mortality was similar in both groups (18.0% versus 17.1% respectively, p = 0.631). Kaplan-Meier curves showed increased early mortality in the SMuRF-less group, but the divergence in survival curves was no longer present in the long-term. The absence of SMuRF was an independent predictor of mortality, regardless of sex or ACS type.In a multi-ethnic cohort of patients with ACS, SMuRF-less patients were observed to have higher mortality than SMuRF patients during the early stages which was attenuated over time.

Prognostic Outcomes in Acute Myocardial Infarction Patients Without Standard Modifiable Risk Factors: A Multiethnic Study of 8,680 Asian Patients.

Background: An increasing proportion of patients with acute myocardial infarction (AMI) are presenting without standard modifiable risk factors (SMuRFs) of hypertension, hypercholesterolemia, diabetes, and smoking, but with an unexpectedly increased mortality. This study examined the SMuRF-less patients presenting with AMI in a multiethnic Asian population. Methods: We recruited patients presenting with AMI from 2011 to 2021 and compared the prevalence, clinical characteristics, and outcomes of SMuRF-less and SMuRF patients. Multivariable analysis was used to compare the outcomes of 30-day cardiovascular mortality, all-cause mortality, readmission, cardiogenic shock, stroke, and heart failure. Kaplan-Meier curves were constructed for 30-day cardiovascular mortality, with stratification by ethnicity, gender and AMI type, and 10-year all-cause mortality. Results: Standard modifiable risk factor-less patients, who made up 8.6% of 8,680 patients, were significantly younger with fewer comorbidities that include stroke and chronic kidney disease, but higher rates of ventricular arrhythmias and inotropic or invasive ventilation requirement. Multivariable analysis showed higher rates of cardiovascular mortality (HR 1.48, 95% CI: 1.09-1.86, p = 0.048), cardiogenic shock (RR: 1.31, 95% CI: 1.09-1.52, p = 0.015), and stroke (RR: 2.51, 95% CI: 1.67-3.34, p = 0.030) among SMuRF-less patients. A 30-day cardiovascular mortality was raised in the SMuRF-less group, with similar trends in men, patients with ST-segment elevation myocardial infarction (STEMI), and the three Asian ethnicities. All-cause mortality remains increased in the SMuRF-less group for up to 5 years. Conclusion: There is a significant proportion of patients with AMI without standard risk factors in Asia, who have worse short-term mortality. This calls for greater focus on the management of this unexpectedly high-risk subgroup of patients.

One-year outcomes of patients with ST-segment elevation myocardial infarction during the COVID-19 pandemic.

The pandemic has led to adverse short-term outcomes for patients with ST-segment elevation myocardial infarction (STEMI). It is unknown if this translates to poorer long-term outcomes. In Singapore, the escalation of the outbreak response on February 7, 2020 demanded adaptation of STEMI care to stringent infection control measures. A total of 321 patients presenting with STEMI and undergoing primary percutaneous coronary intervention at a tertiary hospital were enrolled and followed up over 1-year. They were allocated into three groups based on admission date-(1) Before outbreak response (BOR): December 1, 2019-February 6, 2020, (2) During outbreak response (DOR): February 7-March 31, 2020, and (3) control group: November 1-December 31, 2018. The incidence of cardiac-related mortality, cardiac-related readmissions, and recurrent coronary events were examined. Although in-hospital outcomes were worse in BOR and DOR groups compared to the control group, there were no differences in the 1-year cardiac-related mortality (BOR 8.7%, DOR 7.1%, control 4.8%, p = 0.563), cardiac-related readmissions (BOR 15.1%, DOR 11.6%, control 12.0%, p = 0.693), and recurrent coronary events (BOR 3.2%, DOR 1.8%, control 1.2%, p = 0.596). There were higher rates of additional PCI during the index admission in DOR, compared to BOR and control groups (p = 0.027). While patients admitted for STEMI during the pandemic may have poorer in-hospital outcomes, their long-term outcomes remain comparable to the pre-pandemic era.

Sex differences in assessing stenosis severity between physician visual assessment and quantitative coronary angiography.

BACKGROUND: Physician visual assessment (PVA) in invasive coronary angiography (ICA) is the current clinical method to determine stenosis severity and guide percutaneous coronary intervention. This study sought to evaluate the effect of sex differences in assessing coronary stenosis severity between PVA and quantitative coronary angiography (QCA). METHODS: 209 patients with coronary artery disease (288 coronary lesions) underwent ICA and fractional flow reserve (FFR). ICA image processing including PVA and QCA was used to quantify diameter stenosis (DS). The difference of DS (ΔDS) between PVA and QCA was defined as DSPVA-DSQCA. DS ≥50% was considered anatomically obstructive. FFR ≤0.8 was defined as myocardial ischemia. RESULTS: Mean ± SD age was 63 ± 9 years. There were no significant differences in DSPVA (61.1 ± 16.3% vs 60.1 ± 18.9%) and DSQCA (53.1 ± 12.1% vs 55.4 ± 14.3%) between females and males. However, ΔDS between PVA and QCA was higher in females (8.0 ± 10.9%) than in males (4.7 ± 10.9%) (P = 0.03). Thirty-four of 72 vessels (47.2%) in female patients and 75 of 216 vessels (34.7%) in male patients were classified differently by at least one grade using PVA compared to QCA assessment. DSPVA and DSQCA were negatively correlated with FFR in females (rPVA = -0.397, rQCA = -0.448) with an even stronger negative correlation in males (rPVA = -0.607, rQCA = -0.607). ROC analysis demonstrated that DSQCA had better discrimination capability for myocardial ischemia (FFR ≤ 0.80) than DSPVA in both sexes (P < 0.05). CONCLUSIONS: A systematic bias was found in PVA (QCA reference) for overestimating severity of coronary artery disease in females compared to males.

Diagnostic Performance of Fractional Flow Reserve From CT Coronary Angiography With Analytical Method.

The aim of this study was to evaluate a new analytical method for calculating non-invasive fractional flow reserve (FFRAM) to diagnose ischemic coronary lesions. Patients with suspected or known coronary artery disease (CAD) who underwent computed tomography coronary angiography (CTCA) and invasive coronary angiography (ICA) with FFR measurements from two sites were prospectively recruited. Obstructive CAD was defined as diameter stenosis (DS) ≥50% on CTCA or ICA. FFRAM was derived from CTCA images and anatomical features using analytical method and was compared with computational fluid dynamics (CFD)-based FFR (FFRB) and invasive ICA-based FFR. FFRAM, FFRB, and invasive FFR ≤ 0.80 defined ischemia. A total of 108 participants (mean age 60, range: 30-83 years, 75% men) with 169 stenosed coronary arteries were analyzed. The per-vessel accuracy, sensitivity, specificity, and positive predictive and negative predictive values were, respectively, 81, 75, 86, 81, and 82% for FFRAM and 87, 88, 86, 83, and 90% for FFRB. The area under the receiver operating characteristics curve for FFRAM (0.89 and 0.87) and FFRB (0.90 and 0.86) were higher than both CTCA- and ICA-derived DS (all p < 0.0001) on per-vessel and per-patient bases for discriminating ischemic lesions. The computational time for FFRAM was much shorter than FFRB (2.2 ± 0.9 min vs. 48 ± 36 min, excluding image acquisition and segmentation). FFRAM calculated from a novel and expeditious non-CFD approach possesses a comparable diagnostic performance to CFD-derived FFRB, with a significantly shorter computational time.

Post-ST-Segment Elevation Myocardial Infarction Follow-Up Care During the COVID-19 Pandemic and the Possible Benefit of Telemedicine: An Observational Study.

Background: Infectious control measures during the COVID-19 pandemic have led to the propensity toward telemedicine. This study examined the impact of telemedicine during the pandemic on the long-term outcomes of ST-segment elevation myocardial infarction (STEMI) patients. Methods: This study included 288 patients admitted 1 year before the pandemic (October 2018-December 2018) and during the pandemic (January 2020-March 2020) eras, and survived their index STEMI admission. The follow-up period was 1 year. One-year primary safety endpoint was all-cause mortality. Secondary safety endpoints were cardiac readmissions for unplanned revascularisation, non-fatal myocardial infarction, heart failure, arrythmia, unstable angina. Major adverse cardiovascular events (MACE) was defined as the composite outcome of each individual safety endpoint. Results: Despite unfavorable in-hospital outcomes among patients admitted during the pandemic compared to pre-pandemic era, both groups had similar 1-year all-cause mortality (11.2 vs. 8.5%, respectively, p = 0.454) but higher cardiac-related (14.1 vs. 5.1%, p < 0.001) and heart failure readmissions in the pandemic vs. pre-pandemic groups (7.1 vs. 1.7%, p = 0.037). Follow-up was more frequently conducted via teleconsultations (1.2 vs. 0.2 per patient/year, p = 0.001), with reduction in physical consultations (2.1 vs. 2.6 per patient/year, p = 0.043), during the pandemic vs. pre-pandemic era. Majority achieved guideline-directed medical therapy (GDMT) during pandemic vs. pre-pandemic era (75.9 vs. 61.6%, p = 0.010). Multivariable Cox regression demonstrated achieving medication target doses (HR 0.387, 95% CI 0.164-0.915, p = 0.031) and GDMT (HR 0.271, 95% CI 0.134-0.548, p < 0.001) were independent predictors of lower 1-year MACE after adjustment. Conclusion: The pandemic has led to the wider application of teleconsultation, with increased adherence to GDMT, enhanced medication target dosing. Achieving GDMT was associated with favorable long-term prognosis.

Computed Tomography Coronary Angiography and Computational Fluid Dynamics Based Fractional Flow Reserve Before and After Percutaneous Coronary Intervention.

Invasive fractional flow reserve (FFR) is recommended to guide stent deployment. We previously introduced a non-invasive FFR calculation (FFRB) based on computed tomography coronary angiography (CTCA) with reduced-order computational fluid dynamics (CFD) and resistance boundary conditions. Current study aimed to assess the feasibility and accuracy of FFRB for predicting coronary hemodynamics before and after stenting, with invasive FFR as the reference. Twenty-five patients who had undergone CTCA were prospectively enrolled before invasive coronary angiography (ICA) and FFR-guided percutaneous coronary intervention (PCI) on 30 coronary vessels. Using reduced-order CFD with novel boundary conditions on three-dimensional (3D) patient-specific anatomic models reconstructed from CTCA, we calculated FFRB before and after virtual stenting. The latter simulated PCI by clipping stenotic segments from the 3D coronary models and replacing them with segments to mimic the deployed coronary stents. Pre- and post-virtual stenting FFRB were compared with FFR measured pre- and post-PCI by investigators blinded to FFRB results. Among 30 coronary lesions, pre-stenting FFRB (mean 0.69 ± 0.12) and FFR (mean 0.67 ± 0.13) exhibited good correlation (r = 0.86, p < 0.001) and agreement [mean difference 0.024, 95% limits of agreement (LoA): -0.11, 0.15]. Similarly, post-stenting FFRB (mean 0.84 ± 0.10) and FFR (mean 0.86 ± 0.08) exhibited fair correlation (r = 0.50, p < 0.001) and good agreement (mean difference 0.024, 95% LoA: -0.20, 0.16). The accuracy of FFRB for identifying post-stenting ischemic lesions (FFR ≤ 0.8) (residual ischemia) was 87% (sensitivity 80%, specificity 88%). Our novel FFRB, based on CTCA with reduced-order CFD and resistance boundary conditions, accurately predicts the hemodynamic effects of stenting which may serve as a tool in PCI planning.

A deep learning pipeline for automatic analysis of multi-scan cardiovascular magnetic resonance.

BACKGROUND: Cardiovascular magnetic resonance (CMR) sequences are commonly used to obtain a complete description of the function and structure of the heart, provided that accurate measurements are extracted from images. New methods of extraction of information are being developed, among them, deep neural networks are powerful tools that showed the ability to perform fast and accurate segmentation. Iq1n order to reduce the time spent by reading physicians to process data and minimize intra- and inter-observer variability, we propose a fully automatic multi-scan CMR image analysis pipeline. METHODS: Sequence specific U-Net 2D models were trained to perform the segmentation of the left ventricle (LV), right ventricle (RV) and aorta in cine short-axis, late gadolinium enhancement (LGE), native T1 map, post-contrast T1, native T2 map and aortic flow sequences depending on the need. The models were trained and tested on a set of data manually segmented by experts using semi-automatic and manual tools. A set of parameters were computed from the resulting segmentations such as the left ventricular and right ventricular ejection fraction (EF), LGE scar percentage, the mean T1, T1 post, T2 values within the myocardium, and aortic flow. The Dice similarity coefficient, Hausdorff distance, mean surface distance, and Pearson correlation coefficient R were used to assess and compare the results of the U-Net based pipeline with intra-observer variability. Additionally, the pipeline was validated on two clinical studies. RESULTS: The sequence specific U-Net 2D models trained achieved fast (≤ 0.2 s/image on GPU) and precise segmentation over all the targeted region of interest with high Dice scores (= 0.91 for LV, = 0.92 for RV, = 0.93 for Aorta in average) comparable to intra-observer Dice scores (= 0.86 for LV, = 0.87 for RV, = 0.95 for aorta flow in average). The automatically and manually computed parameters were highly correlated (R = 0.91 in average) showing results superior to the intra-observer variability (R = 0.85 in average) for every sequence presented here. CONCLUSION: The proposed pipeline allows for fast and robust analysis of large CMR studies while guaranteeing reproducibility, hence potentially improving patient's diagnosis as well as clinical studies outcome.

Impact of the COVID-19 Pandemic on Door-to-Balloon Time for Primary Percutaneous Coronary Intervention　- Results From the Singapore Western STEMI Network.

BACKGROUND: Little is known about the effect of the coronavirus disease 2019 (COVID-19) pandemic and the outbreak response measures on door-to-balloon time (D2B). This study examined both D2B and clinical outcomes of patients with STEMI undergoing primary percutaneous coronary intervention (PPCI).Methods and Results:This was a retrospective study of 303 STEMI patients who presented directly or were transferred to a tertiary hospital in Singapore for PPCI from October 2019 to March 2020. We compared the clinical outcomes of patients admitted before (BOR) and during (DOR) the COVID-19 outbreak response. The study outcomes were in-hospital death, D2B, cardiogenic shock and 30-day readmission. For direct presentations, fewer patients in the DOR group achieved D2B time <90 min compared with the BOR group (71.4% vs. 80.9%, P=0.042). This was more apparent after exclusion of non-system delay cases (DOR 81.6% vs. BOR 95.9%, P=0.006). Prevalence of both out-of-hospital cardiac arrest (9.5% vs. 1.9%, P=0.003) and acute mitral regurgitation (31.6% vs. 17.5%, P=0.006) was higher in the DOR group. Mortality was similar between groups. Multivariable regression showed that longer D2B time was an independent predictor of death (odds ratio 1.005, 95% confidence interval 1.000-1.011, P=0.029). CONCLUSIONS: The COVID-19 pandemic and the outbreak response have had an adverse effect on PPCI service efficiency. The study reinforces the need to focus efforts on shortening D2B time, while maintaining infection control measures.

Detection of ADTRP in circulation and its role as a novel biomarker for coronary artery disease.

Androgen dependent tissue factor pathway inhibitor regulating protein (ADTRP) is a novel protein associated with coronary artery disease (CAD) susceptibility, and reduced mRNA expression of ADTRP was shown to be associated with increased CAD risk. This study aimed to determine and compare circulating ADTRP levels between CAD patients and controls, and to test the performance of plasma ADTRP as a biomarker for CAD. We measured plasma ADTRP, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and high sensitivity-C reactive protein (hs-CRP) levels in 362 CAD patients, 150 angiographically negative CAD controls, and 83 healthy adults with no known clinical or medical conditions using commercial ELISA. Statistical analyses were performed using receiver operator characteristic (ROC) curves, quantile regression and logistic regression, with adjustments for age, gender, ethnicity and BMI. CAD patients had significantly lower plasma ADTRP levels 1,545 (1,087-2,408) pg/ml as compared to CAD controls 2,259 (1,533-3,778) pg/ml and healthy adults 3,904 (2,732-5,463) pg/ml. Plasma ADTRP outperformed the other three inflammatory biomarkers (TNF-α, IL-6 and hs-CRP) for CAD (Area under ROC curve: 0.67, Odds ratio (OR): 0.907). Our study has shown for the first time that ADTRP is present in circulation, and that plasma ADTRP may be a novel independent biomarker for CAD.

Variant screening of the serum amyloid A1 gene and functional study of the p.Gly90Asp variant for its role in atherosclerosis.

OBJECTIVES: Serum amyloid A1 (SAA1) is a major acute-phase protein that is increasingly used as a reliable predictor of coronary artery disease (CAD). In this study we aim to screen the SAAI promoter and exons for genetic variants and to determine their association with CAD. In addition, we also carried out functional study on a variant of p.Gly90Asp encoded by the SAA1 gene. METHODS: Variant screening of SAA1 was performed using high resolution melting (HRM) analysis. Genetic association of p.Gly90Asp with CAD was determined in 800 CAD patients and 773 Chinese control subjects. Functional study of p.Gly90Asp was carried out using THP-1-derived macrophages and HL-60 promyelocytic leukemia cells. RESULTS: A total of 6 SNPs were identified, of which 2 were found to be novel (c.-913G > A and c.92-5T > G). The rare allele of p.Gly90Asp has a lower frequency of 0.013 in the CAD patients although this is not statistically significant. Functional studies of p.Gly90Asp revealed that the variant has decreased upregulation of key cytokines such as IL-8, MCP-1 and TNF-α as well as SERPINB2. CONCLUSIONS: We found the variant p.Gly90Asp SAA1 protein eliciting significantly reduced inflammatory responses in macrophages through a reduction in the secretion of inflammatory cytokines. Despite strong functional effects, the minor allele frequency is too low in the population to attain statistical significance difference between cases and controls.

Clinical predictors of stent thrombosis in the "real world" drug-eluting stent era.

BACKGROUND: Drug-eluting stents (DESs) are effective in reducing restenosis and the need for repeat revascularization procedures in patients who undergo percutaneous coronary intervention (PCI). There is however an increased concern with the safety of DES with regard to stent thrombosis (ST). We examined the incidence of ST among patients who received DES and determined the clinical predictors. METHODS: All patients who underwent PCI in our centre were prospectively enrolled in a cardiovascular database. All cases of ST, as defined by 2006 Academic Research Consortium (ARC) hierarchical classification as definite and probable, from August 2002 to August 2006 were reviewed and analyzed. The clinical, angiographic and procedural characteristics of patients who developed ST were compared with those who did not. RESULTS: The study population comprised 1580 patients who received DES implantation. The cumulative incidence of ST was 1.5%: acute ST 0.2%, subacute ST 0.9%, late ST 0.2% and very late ST 0.2%. Mortality and myocardial infarction occurred in 16% and 84% of patients, respectively, as a consequence of ST. Multivariate analysis showed that patients presenting with cardiogenic shock, acute coronary syndrome, presence of multivessel disease, impaired baseline TIMI flow and higher number of stents implanted per lesion were predictive of ST. CONCLUSION: The incidence of DES ST in our 'real world' registry was low. There were clinical and angiographic characteristics identified as independent predictors of ST.