Transcriptomic profiling and regulatory pathways of cardiac resident macrophages in aging.

Cardiovascular diseases are an array of age-related disorders, and accumulating evidence suggests a link between cardiac resident macrophages (CRMs) and the age-related disorders. However, how does CRMs alter with aging remains elusive. In the present study, aged mice (20 months old) have been employed to check for their cardiac structural and functional alterations, and the changes in the proportion of CRM subsets as well, followed by sorting of CRMs, including C-C Motif Chemokine Receptor 2 (CCR2)+ and CCR2- CRMs, which were subjected to Smart-Seq. Integrated analysis of the Smart-Seq data with three publicly available single-cell RNA-seq datasets revealed that inflammatory genes were drastic upregulated for both CCR2+ and CCR2- CRMs with aging, but genes germane to wound healing were downregulated for CCR2- CRMs, suggesting the differential functions of these two subsets. More importantly, inflammatory genes involved in damage sensing, complement cascades, and phagocytosis were largely upregulated in CCR2- CRMs, implying the imbalance of inflammatory response upon aging. Our work provides a comprehensive framework and transcriptional resource for assessing the impact of aging on CRMs with a potential for further understanding cardiac aging.

Interdependence between myocardial deformation and perfusion in patients with T2DM and HFpEF: a feature-tracking and stress perfusion CMR study.

BACKGROUND: Patients with diabetes have an increased risk of developing heart failure with preserved ejection fraction (HFpEF). This study aimed to compare indices of myocardial deformation and perfusion between patients with type 2 diabetes mellitus (T2DM) with and without HFpEF and to investigate the relationship between myocardial strain and perfusion reserve. METHODS: This study included 156 patients with T2DM without obstructive coronary artery disease (CAD) and 50 healthy volunteers who underwent cardiac magnetic resonance (CMR) examination at our center. Patients with T2DM were subdivided into the T2DM-HFpEF (n = 74) and the T2DM-non-HFpEF (n = 82) groups. The parameters of left ventricular (LV) and left atrial (LA) strain as well as stress myocardial perfusion were compared. The correlation between myocardial deformation and perfusion parameters was also assessed. Mediation analyses were used to evaluate the direct and indirect effects of T2DM on LA strain. RESULTS: Patients with T2DM and HFpEF had reduced LV radial peak systolic strain rate (PSSR), LV circumferential peak diastolic strain rate (PDSR), LA reservoir strain, global myocardial perfusion reserve index (MPRI), and increased LA booster strain compared to patients with T2DM without HFpEF (all P < 0.05). Furthermore, LV longitudinal PSSR, LA reservoir, and LA conduit strain were notably impaired in patients with T2DM without HFpEF compared to controls (all P < 0.05), but LV torsion, LV radial PSSR, and LA booster strain compensated for these alterations (all P < 0.05). Multivariate linear regression analysis demonstrated that LA reservoir and LA booster strain were independently associated with global MPRI (ß = 0.259, P < 0.001; ß = - 0.326, P < 0.001, respectively). Further, the difference in LA reservoir and LA booster strain between patients with T2DM with and without HFpEF was totally mediated by global MPRI. Global stress PI, LA booster, global rest PI, and global MPRI showed high accuracy in diagnosing HFpEF among patients with T2DM (areas under the curve [AUC]: 0.803, 0.790, 0.740, 0.740, respectively). CONCLUSIONS: Patients with T2DM and HFpEF exhibited significant LV systolic and diastolic deformation, decreased LA reservoir strain, severe impairment of myocardial perfusion, and elevated LA booster strain that is a compensatory response in HFpEF. Global MPRI was identified as an independent influencing factor on LA reservoir and LA booster strain. The difference in LA reservoir and LA booster strain between patients with T2DM with and without HFpEF was totally mediated by global MPRI, suggesting a possible mechanistic link between microcirculation impairment and cardiac dysfunction in diabetes. Myocardial perfusion and LA strain may prove valuable for diagnosing and managing HFpEF in the future.

TRIM35 triggers cardiac remodeling by regulating SLC7A5-mediated amino acid transport and mTORC1 activation in fibroblasts.

BACKGROUND: Cardiac maladaptive remodeling is one of the leading causes of heart failure with highly complicated pathogeneses. The E3 ligase tripartite motif containing 35 (TRIM35) has been identified as a crucial regulator governing cellular growth, immune responses, and metabolism. Nonetheless, the role of TRIM35 in fibroblasts in cardiac remodeling remains elusive. METHODS: Heart tissues from human donors were used to verify tissue-specific expression of TRIM35. Fibroblast-specific Trim35 gene knockout mice (Trim35cKO) were used to investigate the function of TRIM35 in fibroblasts. Cardiac function, morphology, and molecular changes in the heart tissues were analyzed after transverse aortic constriction (TAC) surgery. The mechanisms by which TRIM35 regulates fibroblast phenotypes were elucidated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and RNA sequencing (RNA-Seq). These findings were further validated through the use of adenoviral and adeno-associated viral transfection systems, as well as the mTORC1 inhibitor Rapamycin. RESULTS: TRIM35 expression is primarily up-regulated in cardiac fibroblasts in both murine and human fibrotic hearts, and responds to TGF-ß1 stimulation. Specific deletion of TRIM35 in cardiac fibroblasts significantly improves cardiac fibrosis and hypertrophy. Consistently, the overexpression of TRIM35 promotes fibroblast proliferation, migration, and differentiation. Through paracrine signaling, it induces hypertrophic growth of cardiomyocytes. Mechanistically, we found that TRIM35 interacts with, ubiquitinates, and up-regulates the amino acid transporter SLC7A5, which enhances amino acid transport and activates the mTORC1 signaling pathway. Furthermore, overexpression of SLC7A5 significantly reverses the reduced cardiac fibrosis and hypertrophy caused by conditional knockout of TRIM35. CONCLUSION: Our findings demonstrate a novel role of fibroblast-TRIM35 in cardiac remodeling and uncover the mechanism underlying SLC7A5-mediated amino acid transport and mTORC1 activation. These results provide a potential novel therapeutic target for treating cardiac remodeling.

Financial and clinical outcomes of CT myocardial perfusion imaging and coronary CT angiography-guided versus coronary CT angiography-guided strategy.

OBJECTIVES: To compare the financial and clinical outcomes of CT myocardial perfusion imaging (CT-MPI) + coronary CT angiography (CCTA)-guided versus CCTA-guided strategy in patients suspected of chronic coronary syndrome (CCS). MATERIALS AND METHODS: This study retrospectively included consecutive patients suspected of CCS and referred for CT-MPI+CCTA-guided and CCTA-guided treatment. The details of medical costs within 3 months after index imaging, including downstream invasive procedures, hospitalization, and medications, were recorded. All patients were followed up for major adverse cardiac events (MACE) at a median time of 22 months. RESULTS: A total of 1335 patients (559 in the CT-MPI+CCTA group and 776 in the CCTA group) were finally included. In the CT-MPI+CCTA group, 129 patients (23.1%) underwent ICA and 95 patients (17.0%) received revascularization. In the CCTA group, 325 patients (41.9%) underwent ICA whereas 194 patients (25.0%) received revascularization. An addition of CT-MPI in the evaluation strategy remarkably reduced the healthcare expenditure, compared with CCTA-guided strategy (USD 1441.36 vs. USD 232.91, p < 0.001). After adjustment for potential cofounders after inverse probability weighting, the CT-MPI+CCTA strategy was significantly associated with lower medical expenditure [adjusted cost ratio (95% CI) for total costs: 0.77 (0.65-0.91), p < 0.001]. In addition, there was no significant difference regarding the clinical outcome between the two groups (adjusted HR= 0.97; p = 0.878). CONCLUSIONS: CT-MPI+CCTA considerably reduced medical expenditures in patients suspected of CCS, compared to the CCTA strategy alone. Moreover, CT-MPI+CCTA led to a lower rate of invasive procedures with a similar long-term prognosis. CLINICAL RELEVANCE STATEMENT: CT myocardial perfusion imaging + coronary CT angiography-guided strategy reduced medical expenditure and invasive procedure rate. KEY POINTS: • CT-MPI+CCTA strategy yielded significantly lower medical expenditure than did the CCTA strategy alone in patients with suspected CCS. • After adjustment for potential confounders, the CT-MPI+CCTA strategy was significantly associated with lower medical expenditure. • No significant difference was observed regarding the long-term clinical outcome between the two groups.

Angiographic quantitative flow ratio-guided coronary intervention (FAVOR III China): a multicentre, randomised, sham-controlled trial.

BACKGROUND: Compared with visual angiographic assessment, pressure wire-based physiological measurement more accurately identifies flow-limiting lesions in patients with coronary artery disease. Nonetheless, angiography remains the most widely used method to guide percutaneous coronary intervention (PCI). In FAVOR III China, we aimed to establish whether clinical outcomes might be improved by lesion selection for PCI using the quantitative flow ratio (QFR), a novel angiography-based approach to estimate the fractional flow reserve. METHODS: FAVOR III China is a multicentre, blinded, randomised, sham-controlled trial done at 26 hospitals in China. Patients aged 18 years or older, with stable or unstable angina pectoris or patients who had a myocardial infarction at least 72 h before screening, who had at least one lesion with a diameter stenosis of 50-90% in a coronary artery with a reference vessel of at least 2·5 mm diameter by visual assessment were eligible. Patients were randomly assigned to a QFR-guided strategy (PCI performed only if QFR ≤0·80) or an angiography-guided strategy (PCI based on standard visual angiographic assessment). Participants and clinical assessors were masked to treatment allocation. The primary endpoint was the 1-year rate of major adverse cardiac events, a composite of death from any cause, myocardial infarction, or ischaemia-driven revascularisation. The primary analysis was done in the intention-to-treat population. The trial was registered with ClinicalTrials.gov (NCT03656848). FINDINGS: Between Dec 25, 2018, and Jan 19, 2020, 3847 patients were enrolled. After exclusion of 22 patients who elected not to undergo PCI or who were withdrawn by their physicians, 3825 participants were included in the intention-to-treat population (1913 in the QFR-guided group and 1912 in the angiography-guided group). The mean age was 62·7 years (SD 10·1), 2699 (70·6%) were men and 1126 (29·4%) were women, 1295 (33·9%) had diabetes, and 2428 (63·5%) presented with an acute coronary syndrome. The 1-year primary endpoint occurred in 110 (Kaplan-Meier estimated rate 5·8%) participants in the QFR-guided group and in 167 (8·8%) participants in the angiography-guided group (difference, -3·0% [95% CI -4·7 to -1·4]; hazard ratio 0·65 [95% CI 0·51 to 0·83]; p=0·0004), driven by fewer myocardial infarctions and ischaemia-driven revascularisations in the QFR-guided group than in the angiography-guided group. INTERPRETATION: In FAVOR III China, among patients undergoing PCI, a QFR-guided strategy of lesion selection improved 1-year clinical outcomes compared with standard angiography guidance. FUNDING: Beijing Municipal Science and Technology Commission, Chinese Academy of Medical Sciences, and the National Clinical Research Centre for Cardiovascular Diseases, Fuwai Hospital.

Recent Evidence on Advances in PCI Treatment for Left Main Coronary Artery Disease.

Revascularization therapy significantly improves the outcomes of patients with left main coronary artery disease (LMCAD), compared with medical therapy alone. For many years, coronary artery bypass grafting (CABG) has been the primary and standard treatment strategy. However, with advances in percutaneous coronary intervention (PCI) techniques and improvements in patients' outcomes, there is growing evidence supporting PCI for LMCAD. In this review, we aim to integrate the available evidences on advances in PCI treatment for LMCAD and provide guidance for further clinical practice.

Nephronectin promotes cardiac repair post myocardial infarction via activating EGFR/JAK2/STAT3 pathway.

Background: ECM proteins are instrumental for angiogenesis, which plays momentous roles during development and repair in various organs, including post cardiac insult. After a screening based on an open access RNA-seq database, we identified Nephronectin (NPNT), an extracellular protein, might be involved in cardiac repair post myocardial infarction (MI). However, the specific impact of nephronectin during cardiac repair in MI remains elusive. Methods and Results: In the present study, we established a system overexpressing NPNT locally in mouse heart by utilizing a recombinant adeno-associated virus. One-to-four weeks post MI induction, we observed improved cardiac function, limited infarct size, alleviated cardiac fibrosis, with promoted angiogenesis in infarct border zone in NPNT overexpressed mice. And NPNT treatment enhanced human umbilical vascular endothelial cell (HUVEC) migration and tube formation, putatively through advocating phosphorylation of EGFR/JAK2/STAT3. The migration and capillary-like tube formation events could be readily revoked by EGFR or STAT3 inhibition. Notably, phosphorylation of EGFR, JAK2 and STAT3 were markedly upregulated in AAV2/9-cTnT-NPNT-treated mice with MI. Conclusions: Our study thus identifies the beneficial effects of NPNT on angiogenesis and cardiac repair post MI by enhancing the EGFR/JAK2/STAT3 signaling pathway, implying the potential therapeutic application of NPNT on myocardial dysfunction post MI.

Diagnostic performance of quantitative, semi-quantitative, and visual analysis of dynamic CT myocardial perfusion imaging: a validation study with invasive fractional flow reserve.

OBJECTIVES: To investigate the diagnostic performance of absolute myocardial blood flow (MBF), MBFratio, and visual analysis of dynamic CT myocardial perfusion imaging (CT-MPI) for the detection of hemodynamically significant coronary stenosis. METHODS: Consecutive patients with chest pain and intermediate-to-high pre-test probability of obstructive coronary artery disease were prospectively enrolled. All patients were referred for dynamic CT-MPI and fractional flow reserve (FFR) measurements within 4 weeks. Absolute MBF, MBFratio (mean MBF of stenosis-subtended territories versus that of reference territories), and visually identified perfusion defect were tested for the diagnostic performance with reference to FFR. RESULTS: Sixty-two patients with 95 target vessels were included for final analysis. The mean radiation dose for dynamic CT-MPI was 3.0 (2.2-4.0) mSv. The mean lesion-based absolute MBF value was significantly lower in ischemic segments than that in non-ischemic segments (78.0 (65.0-86.0) mL/min/100 mL vs. 133.0 (117.5-163.8) mL/min/100 mL, p < 0.001). Similarly, the lesion-based MBFratio was also markedly lower in territories with positive FFR results (0.52 (0.44-0.64) vs. 0.93 (0.91-0.97), p < 0.001). According to per-lesion ROC curve analysis, MBF and MBFratio had a similar area under the curve (AUC) for detecting hemodynamically significant lesions (AUC = 0.942 vs. 0.956, p = 0.413), which were larger than that of visual analysis (AUC = 0.802, both p < 0.01). The vessel-based sensitivity, specificity, and diagnostic accuracy were 84.3%, 97.7%, and 90.5% for MBF and 96.1%, 93.2%, and 94.7% for MBFratio. CONCLUSIONS: Absolute MBF and MBFratio had similarly excellent diagnostic performance with reference to FFR. In addition, these two parameters outperformed visual analysis for the detection of myocardial ischemia. KEY POINTS: • The mean MBF and MBFratio were significantly lower in ischemic segments than those in non-ischemic segments. • Absolute MBF and MBFratio had similar AUCs for the detection of hemodynamically significant lesions (AUC = 0.942 vs. 0.956, p = 0.413), which were larger than that of visual analysis (AUC = 0.802, both p < 0.01). • The vessel-based sensitivity, specificity, and diagnostic accuracy were 84.3%, 97.7%, and 90.5% for absolute MBF and 96.1%, 93.2%, and 94.7% for MBFratio.

Strain parameters for predicting the prognosis of non-ischemic dilated cardiomyopathy using cardiovascular magnetic resonance tissue feature tracking.

BACKGROUND: A considerable number of non-ischemic dilated cardiomyopathy (NDCM) patients had been found to have normalized left ventricular (LV) size and systolic function with tailored medical treatments. Accordingly, we aimed to evaluate if strain parameters assessed by cardiovascular magnetic resonance (CMR) feature tracking (FT) analysis could predict the NDCM recovery. METHODS: 79 newly diagnosed NDCM patients who underwent baseline and follow-up CMR scans were enrolled. Recovery was defined as a current normalized LV size and systolic function evaluated by CMR. RESULTS: Among 79 patients, 21 (27%) were confirmed recovered at a median follow-up of 36 months. Recovered patients presented with faster heart rates (HR) and larger body surface area (BSA) at baseline (P < 0.05). Compared to unrecovered patients, recovered pateints had a higher LV apical radial strain divided by basal radial strain (RSapi/bas) and a lower standard deviation of time to peak radial strain in 16 segments of the LV (SD16-TTPRS). According to a multivariate logistic regression model, RSapi/bas (P = 0.035) and SD16-TTPRS (P = 0.012) resulted as significant predictors for differentiation of recovered from unrecovered patients. The sensitivity and specificity of RSapi/bas and SD16-TTPRS for predicting recovered conditions were 76%, 67%, and 91%, 59%, with the area under the curve of 0.75 and 0.76, respectively. Further, Kaplan Meier survival analysis showed that patients with RSapi/bas ≥ 0.95% and SD16-FTPRS ≤ 111 ms had the highest recovery rate (65%, P = 0.027). CONCLUSIONS: RSapi/bas and CMR SD16-TTPRS may be used as non-invasive parameters for predicting LV recovery in NDCM. This finding may be beneficial for subsequent treatments and prognosis of NDCM patients. Registration number: ChiCTR-POC-17012586.

Research update on the association between SFRP5, an anti-inflammatory adipokine, with obesity, type 2 diabetes mellitus and coronary heart disease.

Secreted frizzled-related protein 5 (SFRP5), an anti-inflammatory adipokine secreted by adipocytes, has been demonstrated to exert its anti-inflammatory effect via antagonizing the non-canonical wingless-type family member 5A (WNT5A) signalling pathways. The WNT5A protein, as a potent pro-inflammatory signalling molecule, is strongly involved in a variety of inflammatory disorders such as obesity, type 2 diabetes mellitus (T2DM) and atherosclerosis. In this review, we systematically outlined the current understanding on the roles of SFRP5 in the pathogenesis of three inflammatory diseases including obesity, T2DM and coronary heart disease (CHD). Our review might stimulate future research using SFRP5 as a promising novel therapeutic target for the treatment of obesity, T2DM and CHD.

The CatLet score and outcome prediction in acute myocardial infarction for patients undergoing primary percutaneous intervention: A proof-of-concept study.

BACKGROUND: The Coronary Artery Tree description and Lesion EvaluaTion (CatLet) score accommodating the variability in coronary anatomy is a recently developed and comprehensive angiographic scoring system aimed at assisting in risk-stratification of patients with coronary artery disease. However, a validation of this angiographic scoring system is lacking. METHODS: The CatLet score was calculated retrospectively in 308 consecutively enrolled patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention. The primary endpoint, major adverse cardiac or cerebrovascular events (MACCEs), was stratified according to CatLet tertiles: CatLetlow ≤14 (n = 124), CatLetmid 15-21 (n = 82) and CatLettop ≥22 (n = 102). RESULTS: The CatLet score alone or after adjusting for a broad spectrum of risk factors, significantly predicted clinical outcomes at a median 4.3-year follow-up. Multivariable-adjusted hazard ratios (95%CI)/unit higher score were 1.05 (1.04-1.07) for MACCE, 1.06 (1.04-1.07) for cardiac death, and 1.05 (1.04-1.07) for all-cause death. When compared to the SYNTAX score, improved discrimination and better calibration of this CatLet score resulted in a significantly refined risk stratification. The overall category-free net reclassification improvement afforded by this CatLet score was as follows: 37.2% (p = .008) for MACCEs, 35.5% (p = .0249) for cardiac death, and 31.8% (p = .0316) for all-cause death. CONCLUSIONS: The ability to integrate the variability in coronary anatomy into angiographic scoring makes the CatLet score a more specific tool for outcome predictions in AMI. (http://www.chictr.org.cn. Unique identifiers: ChiCTR-POC-17013536).

Diagnostic performance of perivascular fat attenuation index to predict hemodynamic significance of coronary stenosis: a preliminary coronary computed tomography angiography study.

OBJECTIVE: This study aimed to investigate the association between perivascular fat attenuation index (FAI) and hemodynamic significance of coronary lesions. METHODS: Patients with stable angina who underwent coronary computed tomography (CT) angiography and invasive fractional flow reserve (FFR) measurement within 2 weeks were retrospectively included. Lesion-based perivascular FAI, high-risk plaque features, total plaque volume (TPV), machine learning-based FFRCT, and other parameters were recorded. Lesions with invasive FFR ≤ 0.8 were considered functionally significant. RESULTS: This study included 167 patients with 219 lesions. Diameter stenosis (DS), lesion length, TPV, and perivascular FAI were significantly larger or longer in the group of hemodynamically significant lesions (FFR ≤ 0.8). In addition, smaller FFRCT value was associated with functionally significant lesions (0.720 ± 0.11 vs 0.846 ± 0.10, p < 0.001). No significant difference was found between the hemodynamically significant and insignificant subgroups with respect to CT-derived high-risk plaque features. According to multivariate analysis, DS, TPV, and perivascular FAI were significant predictors of lesion-specific ischemia. When integrating DS, TPV, and perivascular FAI, the area under the curve (AUC) of this combined method was 0.821, which was similar to that of FFRCT (AUC, 0.821 vs 0.850; p = 0.426). The diagnostic accuracy of FFRCT was higher than that of the combined approach, but the difference was statistically insignificant (79.0% vs 74.0%, p = 0.093). CONCLUSIONS: Perivascular FAI was significantly higher for flow-limiting lesions than for non-flow-limiting lesions. The combined use of FAI, TPV, and DS could predict ischemic coronary stenosis with high diagnostic accuracy. KEY POINTS: • Perivascular FAI was significantly higher for flow-limiting lesions than for non-flow-limiting lesions. • Combined use of FAI, plaque volume, and DS provided diagnostic performance comparable to that of machine learning-based FFR CTfor predicting ischemic coronary stenosis. • No significant difference was found between the hemodynamically significant and insignificant subgroups with respect to CT-derived high-risk plaque features.

Detection of Hemodynamically Significant Coronary Stenosis: CT Myocardial Perfusion versus Machine Learning CT Fractional Flow Reserve.

Background Direct intraindividual comparison of dynamic CT myocardial perfusion imaging (MPI) and machine learning (ML)-based CT fractional flow reserve (FFR) has not been explored for diagnosing hemodynamically significant coronary artery disease. Purpose To investigate the diagnostic performance of dynamic CT MPI and ML-based CT FFR for functional assessment of coronary stenosis. Materials and Methods Between January 2, 2017, and October 17, 2018, consecutive participants with stable angina were prospectively enrolled. All participants underwent dynamic CT MPI coronary CT angiography and invasive conventional coronary angiography (CCA) FFR within 2 weeks. Receiver operating characteristic (ROC) curve analysis was used to assess diagnostic performance. Results Eighty-six participants (mean age, 67 years ± 12 [standard deviation]; 67 men) with 157 target vessels were included for final analysis. The mean radiation doses for dynamic CT MPI and coronary CT angiography were 3.6 mSv ± 1.1 and 2.7 mSv ± 0.8, respectively. Myocardial blood flow (MBF) was lower in ischemic segments compared with nonischemic segments and reference segments (defined as the territory of vessels without stenosis) (75 mL/100 mL/min ± 20 vs 148 mL/100 mL/min ± 22 and 169 mL/100 mL/min ± 34, respectively, both P < .001). Similarly, CT FFR was also lower for hemodynamically significant lesions than for hemodynamically nonsignificant lesions (0.68 ± 0.1 vs 0.83 ± 0.1, respectively, P < .001). MBF had the largest area under the ROC curve (AUC) (using 99 mL/100 mL/min as a cutoff) among all parameters, outperforming ML-based CT FFR (AUC = 0.97 vs 0.85, P < .001). The vessel-based specificity and diagnostic accuracy of MBF were higher than those of ML-based CT FFR (93% vs 68%, P < .001 and 94% vs 78%, respectively, P = .04) whereas the sensitivity of both methods was similar (96% vs 88%, respectively, P = .11). Conclusion Dynamic CT myocardial perfusion imaging was able to help accurately evaluate the hemodynamic significance of coronary stenosis using a reduced amount of radiation. In addition, the myocardial blood flow derived from dynamic CT myocardial perfusion imaging outperformed machine learning-based CT fractional flow reserve for identifying lesions causing ischemia. © RSNA, 2019 Online supplemental material is available for this article.See also the editorial by Loewe in this issue.

The best predictor of ischemic coronary stenosis: subtended myocardial volume, machine learning-based FFRCT, or high-risk plaque features?

OBJECTIVES: The present study aimed to compare the diagnostic performance of a machine learning (ML)-based FFRCT algorithm, quantified subtended myocardial volume, and high-risk plaque features for predicting if a coronary stenosis is hemodynamically significant, with reference to FFRICA. METHODS: Patients who underwent both CCTA and FFRICA measurement within 2 weeks were retrospectively included. ML-based FFRCT, volume of subtended myocardium (Vsub), percentage of subtended myocardium volume versus total myocardium volume (Vratio), high-risk plaque features, minimal lumen diameter (MLD), and minimal lumen area (MLA) along with other parameters were recorded. Lesions with FFRICA ≤ 0.8 were considered to be functionally significant. RESULTS: One hundred eighty patients with 208 lesions were included. The lesion length (LL), diameter stenosis, area stenosis, plaque burden, Vsub, Vratio, Vratio/MLD, Vratio/MLA, and LL/MLD4 were all significantly longer or larger in the group of FFRICA ≤ 0.8 while smaller minimal lumen area, MLD, and FFRCT value were noted. The AUC of FFRCT + Vratio/MLD was significantly better than that of FFRCT alone (0.935 versus 0.873, p < 0.001). High-risk plaque features failed to show difference between functionally significant and insignificant groups. Vratio/MLD-complemented ML-based FFRCT for "gray zone" lesions with FFRCT value ranged from 0.7 to 0.8 and the combined use of these two parameters yielded the best diagnostic performance (86.5%, 180/208). CONCLUSIONS: ML-based FFRCT simulation and Vratio/MLD both provide incremental value over CCTA-derived diameter stenosis and high-risk plaque features for predicting hemodynamically significant lesions. Vratio/MLD is more accurate than ML-based FFRCT for lesions with simulated FFRCT value from 0.7 to 0.8. KEY POINTS: • Machine learning-based FFR CT and subtended myocardium volume both performed well for predicting hemodynamically significant coronary stenosis. • Subtended myocardium volume was more accurate than machine learning-based FFR CT for "gray zone" lesions with simulated FFR value from 0.7 to 0.8. • CT-derived high-risk plaque features failed to correctly identify hemodynamically significant stenosis.

Image quality and diagnostic accuracy of coronary CT angiography derived from low-dose dynamic CT myocardial perfusion: a feasibility study with comparison to invasive coronary angiography.

OBJECTIVES: To investigate the diagnostic performance of coronary CT angiography derived from dynamic CT myocardial perfusion imaging (CCTACT-MPI) by third-generation dual-source CT with reference to invasive coronary angiography (ICA). MATERIALS AND METHODS: Patients with acute myocardial infarction and those who received successful reperfusion treatment were prospectively enrolled. Emergent ICA findings were used as the reference standard to assess the diagnostic performance of CCTACT-MPI for detection of significant coronary stenosis (diameter stenosis ≥ 50%). The radiation dose as well as image quality of CCTACT-MPI was also assessed. RESULTS: Twenty-six patients with 352 segments were ultimately included for analysis. The mean radiation dose of CCTACT-MPI generated from dynamic CT-MPI was 3.2 ± 1.1 mSv. Overall, 93.5% of total segments were interpretable (Likert score 2-4) whereas 6.5% segments were non-diagnostic (Likert score 1). Twenty-two patients with 84 segments were diagnosed by CCTACT-MPI as having ≥ 50% stenosis presence, whereas 268 segments had no obstructive stenosis. Compared to ICA findings, the overall diagnostic accuracy of CCTACT-MPI of patient-based and vessel-based as well segment-based analysis was 92.3%, 83.6%, and 85.8% respectively. As shown by ROC analysis, the AUC of CCTACT-MPI for detection of ≥ 50% stenosis was 0.833 on a per-patient level, 0.843 on a per-vessel level, and 0.822 on a per-segment level. CONCLUSIONS: CCTACT-MPI derived from dynamic CT-MPI was able to accurately diagnose obstructive coronary stenosis with reference to ICA. KEY POINTS: • CCTA derived from dynamic CT-MPI had a diagnostic image quality in 93.5% of total segments. • CCTA derived from dynamic CT-MPI was accurate in diagnosing obstructive CAD compared to ICA. • The mean radiation dose of dynamic CT-MPI for reconstruction of CCTA was 3.2 mSv.

Evaluation of elevated left ventricular end diastolic pressure in patients with preserved ejection fraction using cardiac magnetic resonance.

OBJECTIVES: This study aims to validate the reliability of cardiac magnetic resonance (CMR) parameters for estimating left ventricular end diastolic pressure (LVEDP) in heart failure patients with preserved ejection fraction (HFpEF) and compare their accuracy to conventional echocardiographic ones, with reference to left heart catheterisation. METHODS: Sixty patients with exertional dyspnoea (New York Heart Association function class II to III) were consecutively enrolled. CMR-derived time-volume curve and deformation parameters, conventional echocardiographic diastolic indices as well as LVEDP evaluated by left heart catheterisation were collected and analysed. RESULTS: Fifty-one patients, who accomplished all three examinations, were divided into HFpEF group and non-HFpEF group based on LVEDP measurements. Compared to the non-HFpEF group, CMR-derived time-volume curve showed lower peak filling rate adjusted for end diastolic volume (PFR/EDV, p = 0.027), longer time to peak filling rate (T-PFR, p < 0.001), and increased T-PFR in one cardiac cycle (%T-PFR, p < 0.001) in HFpEF group. In multivariable linear regression analysis, %T-PFR (ß = 0.372, p = 0.024), left ventricular global peak longitudinal diastolic strain rate (LDSR, ß = -0.471, p = 0.006), and E/e' (ß = 0.547, p = 0.001) were independently associated with invasively measured LVEDP. The sensitivity and specificity of E/e' and LDSR for predicting the elevated LVEDP were 76%, 92% and 76%, 89%, respectively. CONCLUSIONS: These findings suggest that CMR-derived time-volume curve and strain indices could predict HFpEF patients. Not only E/e' assessed by echocardiography but also the CMR-derived %T-PFR and LDSR correlated well with LVEDP. These non-invasive parameters were validated to evaluate the left ventricular diastolic function. KEY POINTS: • The abnormal time-volume curve revealed insufficient early diastole in HFpEF patients. • Non-invasive parameters including E/e', %T-PFR, and LDSR correlated well with LVEDP.

Amphiregulin enhances cardiac fibrosis and aggravates cardiac dysfunction in mice with experimental myocardial infarction partly through activating EGFR-dependent pathway.

Cardiac fibrosis (CF), a main process of ventricular remodeling after myocardial infarction (MI), plays a crucial role in the pathogenesis of heart failure (HF) post-MI. It is known that amphiregulin (AR) is involved in fibrosis of several organs. However, the expression of AR and its role post-MI are yet to be determined. This study aimed to investigate the impact of AR on CF post-MI and related mechanisms. Significantly upregulated AR expression was evidenced in the infarct border zone of MI mice in vivo and the AR secretion was enhanced in macrophages, but not in cardiac fibroblasts. In vitro, treatment with AR increased cardiac fibroblast migration, proliferation and collagen synthesis, and upregulated the expression of epidermal growth factor receptor (EGFR) and the downstream genes such as Akt, ERK1/2 and Samd2/3 on cardiac fibroblasts. All these effects could be abrogated by pretreatment with a specific EGFR inhibitor. To verify the functions of AR in MI hearts, lentivirus-AR-shRNA and negative control vectors were delivered into the infarct border zone. After 28 days, knock-down of AR increased the survival rate and improved cardiac function, while decreasing the extent of myocardial fibrosis of MI mice. Moreover, EGFR and the downstream genes were significantly downregulated in lentivirus-AR-shRNA treated MI mice. Our results thus indicate that AR plays an important role in promoting CF after MI partly though activating the EGFR pathway. Targeting AR might be a novel therapeutic option for attenuating CF and improve cardiac function after MI.

Noninvasive and prospective diagnosis of coronary heart disease with urine using surface-enhanced Raman spectroscopy.

A prospective diagnosis method for coronary heart disease (CHD) using human urine based on surface-enhanced Raman spectroscopy (SERS) is proposed, and could provide valuable information for judging whether to perform percutaneous coronary intervention (PCI) in clinics. Here, urine samples from 87 patients with CHD, including patients with PCI before operation (degree of cardiovascular congestion above 70%) and without PCI (degree of cardiovascular congestion under 70%), and 20 healthy humans were measured using SERS. Principal component analysis (PCA) combined with linear discriminant analysis (LDA) was employed to analyze the SERS spectra, revealing that the classification sensitivity and specificity were 90% and 78.9%, respectively, and the absolute value for loading of PC1 at 1509 cm-1 was the largest. Since platelet-derived growth factor-BB (PDGF-BB) is closely related to CHD, PDGF-BB aqueous solutions with various concentrations (1, 0.5, 0.1, 0.05 and 0.01 ppm) and a mixture of healthy human urine and PDGF-BB aqueous solutions were then investigated in this work, and it was found that the Raman peak at 1509 cm-1 may be attributed to PDGF-BB. Moreover, the measured SERS spectra of all the urine samples from the 87 patients with CHD were compared with the clinical data provided by a hospital, and it was revealed that the appearance of a peak at 1509 cm-1 in the SERS spectra was in good agreement with the results of coronary angiography tests when cardiovascular congestion was above 70%. This indicated that the classification sensitivity and specificity were 87.9% and 87.0%, respectively, through identification of the Raman peak at 1509 cm-1.

Diastolic dysfunction predicts the risk of contrast-induced nephropathy and outcome post-emergency percutaneous coronary intervention in AMI patients with preserved ejection fraction.

Patients with acute myocardial infarction (AMI) and reduced left ventricular ejection fraction (LVEF) are at high risk of contrast-induced nephropathy (CIN). However, the risk factors of CIN in AMI patients with preserved LVEF remain largely unknown now. The present study explored the relationship between LV diastolic function and CIN in this patient cohort. The present prospective cohort study enrolled 379 AMI patients with preserved LVEF (≥ 50%) who underwent emergency percutaneous coronary interventions (PCI). Transthoracic echocardiography was performed before PCI using a portable echocardiography system. Diastolic function was graded as normal, indeterminate and diastolic dysfunction according to the current recommendation of the American Society of Echocardiography and the European Association of Cardiovascular Imaging. A total of 88 patients (23.2%) developed CIN. Multivariate logistic regression analysis showed that both diastolic dysfunction (DD) and the mitral E velocity to mitral annular tissue Doppler E' velocity ratio (E/E') were independent predictors of CIN (P < 0.001). Other independent risk factors of CIN included increased Mehran score, ST-segment-elevation myocardial infarction, higher HbA1c and left anterior descending lesion, as well as the use of diuretics. Multivariate Cox regression analysis found that CIN, DD, higher N-terminal pro-B-type natriuretic peptide and HbA1c were independent predictors of MACE 2 years after AMI. Diastolic dysfunction determined before emergency PCI is linked with increased risk of CIN in AMI patients with preserved LVEF. CIN and diastolic dysfunction are independent predictors of MACE at 2 years in this patient cohort.

Exosomes Derived from Mesenchymal Stem Cells Rescue Myocardial Ischaemia/Reperfusion Injury by Inducing Cardiomyocyte Autophagy Via AMPK and Akt Pathways.

BACKGROUND/AIMS: Reperfusion after an ischaemic insult might cause infarct extension. Mesenchymal stem cell (MSC)-derived exosomes could attenuate myocardial remodelling in animal models of myocardial ischaemia reperfusion injury (MIRI), and the present study aimed to explore the related mechanisms. METHODS: In vitro, rat H9C2 cardiomyocytes (H9C2s) were exposed to H2O2. Cell viability was detected by the CCK-8 assay, apoptosis was detected by Annexin V-PE/7-AAD staining, ROS production was detected by fluorescence microscopy and flow cytometry, and apoptosis-related proteins and signalling pathway-related proteins were detected by western blot analysis. Autophagic flux was measured using the tandem fluorescent mRFG-GFP-LC3 assay. MSC-derived exosomes were extracted using the total exosome isolation reagent. Apoptosis, myocardial infarction size, heart function and myocardial LC3B expression were examined in an in vivo I/R model by the TUNEL assay, TTC/Evan blue staining, echocardiography and immunohistochemicalstaining, respectively. RESULTS: In vitro, H2O2 dose-dependently increased ROS production and cell apoptosis in H9C2s and blocked autophagic flux after 3 h of exposure; autophagy gradually decreased thereafter, and the lowest level was detected at 12 h after exposure. MSC-derived exosomes reduced H2O2-induced ROS production and cell apoptosis and enhanced autophagy at 12 h after exposure. In H9C2 cells exposed to H2O2 for 12 h, treatment with exosomes enhanced autophagy via the AMPK/mTOR and Akt/mTOR pathways. Likewise, in vivo exosome injections in rats that underwent I/R injury significantly reduced apoptosis and the myocardial infarct size and upregulated myocardial LC3B expression as well as improved heart function. CONCLUSIONS: Our results indicate that MSC-derived exosomes could reduce MIRI by inducing cardiomyocyte autophagy via AMPK/mTOR and Akt/mTOR pathways.