Radiomics-based discrimination of coronary chronic total occlusion and subtotal occlusion on coronary computed tomography angiography.

OBJECTIVES: Differentiating chronic total occlusion (CTO) from subtotal occlusion (SO) is often difficult to make from coronary computed tomography angiography (CCTA). We developed a CCTA-based radiomics model to differentiate CTO and SO. METHODS: A total of 66 patients with SO underwent CCTA before invasive angiography and were matched to 66 patients with CTO. Comprehensive imaging analysis was conducted for all lesioned vessels, involving the automatic identification of the lumen within the occluded segment and extraction of 1,904 radiomics features. Radiomics models were then constructed to assess the discriminative value of these features in distinguishing CTO from SO. External validation of the model was performed using data from another medical center. RESULTS: Compared to SO patients, CTO patients had more blunt stumps (internal: 53/66 (80.3%) vs. 39/66 (59.1%); external: 36/50 (72.0%) vs. 20/50 (40.0%), both p < 0.01), longer lesion length (internal: median length 15.4 mm[IQR: 10.4-22.3 mm] vs. 8.7 mm[IQR: 4.9-12.6 mm]; external:11.8 mm[IQR: 6.1-23.4 mm] vs. 6.2 mm[IQR: 3.5-9.1 mm]; both p < 0.001). Sixteen unique radiomics features were identified after the least absolute shrinkage and selection operator regression. When added to the combined model including imaging features, radiomics features provided increased value for distinguishing CTO from SO (AUC, internal: 0.772 vs. 0.846; p = 0.023; external: 0.718 vs. 0.781, p = 0.146). CONCLUSIONS: The occluded segment vessels of CTO and SO have different radiomics signatures. The combined application of radiomics features and imaging features based on CCTA extraction can enhance diagnostic confidence.

PU.1 inhibition does not attenuate cardiac function deterioration or fibrosis in a murine model of myocardial infarction.

Activated cardiac fibroblasts are involved in both reparative wound healing and maladaptive cardiac fibrosis after myocardial infarction (MI). Recent evidence suggests that PU.1 inhibition can enable reprogramming of profibrotic fibroblasts to quiescent fibroblasts, leading to attenuation of pathologic fibrosis in several fibrosis models. The role of PU.1 in acute MI has not been tested. We designed a randomized, blinded study to evaluate whether DB1976, a PU.1 inhibitor, attenuates cardiac function deterioration and fibrosis in a murine model of MI. A total of 44 Ai9 periostin-Cre transgenic mice were subjected to 60 min of coronary occlusion followed by reperfusion. At 7 days after MI, 37 mice were randomly assigned to control (vehicle) or DB1976 treatment and followed for 2 weeks. Left ventricular ejection fraction (EF), assessed by echocardiography, did not differ between the two groups before or after treatment (final EF, 33.3 ± 1.0% in control group and 31.2 ± 1.3% in DB1976 group). Subgroup analysis of female and male mice showed the same results. There were no differences in cardiac scar (trichrome stain) and fibrosis (interstitial/perivascular collagen; picrosirius stain) between groups. Results from the per-protocol dataset (including mice with pre-treatment EF < 35% only) were consistent with the full dataset. In conclusion, this randomized, blinded study demonstrates that DB1976, a PU.1 inhibitor, does not attenuate cardiac functional deterioration or cardiac fibrosis in a mouse model of MI caused by coronary occlusion/reperfusion.

Common coronary artery occlusions in patients with myocardial infarction.

Introduction: coronary artery disease (CAD) is a significant cardiovascular disease (CVD) that affects people worldwide. This study aimed to determine the main occluded coronary arteries in patients with myocardial infarction in Najran, Kingdom of Saudi Arabia (KSA). Methods: a retrospective cross-sectional study conducted between March 2020 and March 2021 and involving 661 myocardial infarction patients recruited from two hospitals (King Khalid Hospital and Prince Sultan Centre for Healthcare in Najran) used sampling for enrolled patients. Patients over the age of 15 years, current residents of KSA, and diagnosed with coronary artery occlusion based on at least one identifiable coronary lesion on a coronary angiography were considered eligible. We created generalized linear mixed models to investigate patients´ clinical and coronary angiographic features and identify statistically relevant components. Results: there were 661 CAD cases in this study: 548 (82.9%) males and 113 (17.1%) females, with a mean and standard deviation (SD) age of 4.03 ± 1.370 years. Ages of the 661 participants ranged from 15 to 85, who had been diagnosed with myocardial infarction were evaluated. It was found that most of the patients were in the 55-64 age range. The majority of cases (366 (55.4%) had ST-segment elevation myocardial infarction (STEMI), 187 (28.3%) had non-ST-segment elevation (NSTEMI), 101 (15.3%) had acute coronary syndrome-non-ST-segment elevation (ACS-NSTEMI), and 7 (1.1%) had acute coronary syndrome-ST-segment elevation (ACS-STEMI). Conclusion: the left anterior descending artery (LAD) is the commonest lesion found in both ST-segment elevation and non-ST-segment elevation myocardial infarction patients.

ST-segment resolution as a marker for severe myocardial fibrosis in ST-segment elevation myocardial infarction.

OBJECTIVE: To investigate the relationship between ST-segment resolution (STR) and myocardial scar thickness after percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: Forty-two STEMI patients with single-branch coronary artery stenosis or occlusion were enrolled. ST-segment elevations were measured at emergency admission and at 24 h after PCI. Late gadolinium-enhanced cardiac magnetic resonance imaging (CMR-LGE) was performed 7 days after PCI to evaluate myocardial scars. Statistical analyses were performed to assess the utility of STR to predict the development of transmural (> 75%) or non-transmural (< 75%) myocardial scars, according to previous study. RESULTS: The sensitivity and specificity of STR for predicting transmural scars were 96% and 88%, respectively, at an STR cut-off value of 40.15%. The area under the curve was 0.925. Multivariate logistic proportional hazards regression analysis disclosed that patients with STR < 40.15% had a 170.90-fold higher probability of developing transmural scars compared with patients with STR ≥ 40.15%. Pearson correlation and linear regression analyses showed STR percentage was significantly associated with myocardial scar thickness and size. CONCLUSION: STR < 40.15% at 24 h after PCI may provide meaningful diagnostic information regarding the extent of myocardial scarification in STEMI patients.

Detection of myocardial ischemia by intracoronary ECG using convolutional neural networks.

INTRODUCTION: The electrocardiogram (ECG) is a valuable tool for the diagnosis of myocardial ischemia as it presents distinctive ischemic patterns. Deep learning methods such as convolutional neural networks (CNN) are employed to extract data-derived features and to recognize natural patterns. Hence, CNN enable an unbiased view on well-known clinical phenomenon, e.g., myocardial ischemia. This study tested a novel, hypothesis-generating approach using pre-trained CNN to determine the optimal ischemic parameter as obtained from the highly susceptible intracoronary ECG (icECG). METHOD: This was a retrospective observational study in 228 patients with chronic coronary syndrome. Each patient had participated in clinical trials with icECG recording and ST-segment shift measurement at the beginning (i.e., non-ischemic) and the end (i.e., ischemic) of a one-minute proximal coronary artery balloon occlusion establishing the reference. Using these data (893 icECGs in total), two pre-trained, open-access CNN (GoogLeNet/ResNet101) were trained to recognize ischemia. The best performing CNN during training were compared with the icECG ST-segment shift for diagnostic accuracy in the detection of artificially induced myocardial ischemia. RESULTS: Using coronary patency or occlusion as reference for absent or present myocardial ischemia, receiver-operating-characteristics (ROC)-analysis of manually obtained icECG ST-segment shift (mV) showed an area under the ROC-curve (AUC) of 0.903±0.043 (p<0.0001, sensitivity 80%, specificity 92% at a cut-off of 0.279mV). The best performing CNN showed an AUC of 0.924 (sensitivity 93%, specificity 92%). DeLong-Test of the ROC-curves showed no significant difference between the AUCs. The underlying morphology responsible for the network prediction differed between the trained networks but was focused on the ST-segment and the T-wave for myocardial ischemia detection. CONCLUSIONS: When tested in an experimental setting with artificially induced coronary artery occlusion, quantitative icECG ST-segment shift and CNN using pathophysiologic prediction criteria detect myocardial ischemia with similarly high accuracy.

Complex Coronary Instent Chronic Total Occlusion Lesions: Oxidative Stress, Inflammation, and Coronary Stent Lengths.

The oxidative stress and inflammation played the key roles in the development of atherosclerotic coronary plaques. However, the relationships between pro/antioxidant, pro/anti-inflammatory status, and complex coronary instent chronic total occlusion lesions were not clear in the elderly patients with very long stent implantations. We tried to evaluate the roles of pro/antioxidant and pro/anti-inflammatory biomarkers in the diagnosis of complex reocclusion lesions in elderly patients after coronary stenting. We evaluated the expression levels of acrolein (ACR), malondialdehyde (MDA), high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), superoxide dismutase 3 (SOD3), paraoxonase-1 (PON-1), endothelial nitric oxide synthase (eNOS), and stromal cell-derived factor-1α (SDF-1α) in the elderly patients with very long stent implantations and complex reocclusion lesions. Levels of ACR, MDA, hs-CRP, and TNF-α were remarkably increased (P < 0.001), and levels of SOD3, PON-1, eNOS, and SDF-1α were decreased significantly (P < 0.001) in the elderly patients with very long stents and complex reocclusion lesions. The prooxidant and proinflammatory biomarkers were remarkably increased, as well as antioxidant and anti-inflammatory biomarkers were decreased significantly in the elderly patients with very long stent implantations and complex reocclusion lesions after coronary stenting. In conclusion, these findings indicated that the imbalance between prooxidant/proinflammatory and antioxidant/anti-inflammatory status was associated with complex reocclusion lesions, suggesting that oxidative stress and inflammation played the key roles in progression of complex reocclusion lesions in the elderly patients with very long stent implantations.

Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response. OBJECTIVES: This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI. METHODS: The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days. RESULTS: We randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups. CONCLUSIONS: Tocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703).

Citric Acid Cycle Metabolites Predict Infarct Size in Pigs Submitted to Transient Coronary Artery Occlusion and Treated with Succinate Dehydrogenase Inhibitors or Remote Ischemic Perconditioning.

Succinate dehydrogenase (SDH) inhibition with malonate during reperfusion reduced myocardial infarction in animals, whereas its endogenous substrate, succinate, is detected in plasma from STEMI patients. We investigated whether protection by SDH inhibition is additive to that of remote ischemic perconditioning (RIC) in pigs submitted to transient coronary artery occlusion, and whether protective maneuvers influence plasma levels of citric acid cycle metabolites. Forty pigs were submitted to 40 min coronary occlusion and reperfusion, and allocated to four groups (controls, sodium malonate 10 mmol/L, RIC, and malonate + RIC). Plasma was obtained from femoral and great cardiac veins and analyzed by LC-MS/MS. Malonate, RIC, and malonate + RIC reduced infarct size (24.67 ± 5.98, 25.29 ± 3.92 and 29.83 ± 4.62% vs. 46.47 ± 4.49% in controls, p < 0.05), but no additive effects were detected. Enhanced concentrations of succinate, fumarate, malate and citrate were observed in controls during initial reperfusion in the great cardiac vein, and most were reduced by cardioprotective maneuvers. Concentrations of succinate, fumarate, and malate significantly correlated with infarct size. In conclusion, despite the combination of SDH inhibition during reperfusion and RIC did not result in additive protection, plasma concentrations of selected citric acid cycle metabolites are attenuated by protective maneuvers, correlate with irreversible injury, and might become a prognosis tool in STEMI patients.

CT Angiography-Derived RECHARGE Score Predicts Successful Percutaneous Coronary Intervention in Patients with Chronic Total Occlusion.

OBJECTIVE: To investigate the feasibility and the accuracy of the coronary CT angiography (CCTA)-derived Registry of Crossboss and Hybrid procedures in France, the Netherlands, Belgium and United Kingdom (RECHARGE) score (RECHARGECCTA) for the prediction of procedural success and 30-minutes guidewire crossing in percutaneous coronary intervention (PCI) for chronic total occlusion (CTO). MATERIALS AND METHODS: One hundred and twenty-four consecutive patients (mean age, 54 years; 79% male) with 131 CTO lesions who underwent CCTA before catheter angiography (CA) with CTO-PCI were retrospectively enrolled in this study. The RECHARGECCTA scores were calculated and compared with RECHARGECA and other CTA-based prediction scores, including Multicenter CTO Registry of Japan (J-CTO), CT Registry of CTO Revascularisation (CT-RECTOR), and Korean Multicenter CTO CT Registry (KCCT) scores. RESULTS: The procedural success rate of the CTO-PCI procedures was 72%, and 61% of cases achieved the 30-minutes wire crossing. No significant difference was observed between the RECHARGECCTA score and the RECHARGECA score for procedural success (median 2 vs. median 2, p = 0.084). However, the RECHARGECCTA score was higher than the RECHARGECA score for the 30-minutes wire crossing (median 2 vs. median 1.5, p = 0.001). The areas under the curve (AUCs) of the RECHARGECCTA and RECHARGECA scores for predicting procedural success showed no statistical significance (0.718 vs. 0.757, p = 0.655). The sensitivity, specificity, positive predictive value, and the negative predictive value of the RECHARGECCTA scores of ≤ 2 for predictive procedural success were 78%, 60%, 43%, and 87%, respectively. The RECHARGECCTA score showed a discriminative performance that was comparable to those of the other CTA-based prediction scores (AUC = 0.718 vs. 0.665-0.717, all p > 0.05). CONCLUSION: The non-invasive RECHARGECCTA score performs better than the invasive determination for the prediction of the 30-minutes wire crossing of CTO-PCI. However, the RECHARGECCTA score may not replace other CTA-based prediction scores for predicting CTO-PCI success.

Autopsy Cardiac Troponin I Plasma Levels Can Be Elevated in Myocardial Infarction Type 3: A Proposal to Modify the Definition of Myocardial Infarction Type 3.

AIMS: The definition of myocardial infarction (MI) type 3 does not include the possible elevation of postmortem biomarkers if measured at autopsy. We determined postmortem cardiac troponin I (cTnI) levels in plasma samples obtained at autopsy in patients who died from MI type 3 to determine whether cTnI plasma levels may be elevated. METHODS AND RESULTS: Using a chemiluminescent microparticle immunoassay system, we determined postmortem cTnI plasma levels at autopsy performed within 24 hours of death in every decedent who died from MI type 3, confirmed by an autopsy. Over 2 years, autopsy confirmed 52 decedents who died from MI type 3 due to coronary atherosclerotic disease. The age range and mean age were 40 to 78 and 60.6 years, respectively, 38 (73%) men and 14 (27%) women. Ten percent of the decedents exhibited postmortem cTnI plasma levels that were within the normal reference levels (0.01-0.30 ng/mL). Ninety percent of the decedents exhibited elevated cTnI plasma levels at autopsy, which ranged from 0.31 to greater than 4400 ng/mL. Sixty-nine percent of our decedents showed severe/significant (75%-100%) luminal occlusion in 2 or 3 major coronary arteries. CONCLUSIONS: If cTnI plasma levels are measured in autopsy blood samples after sudden and unexpected death due to MI type 3, highly elevated cTnI plasma levels may be detected. We propose that the current MI type 3 definition be slightly modified to include the possible elevation of cTnI plasma levels if measured at autopsy in the immediate postmortem period.

Can the degree of coronary collateralization be used in clinical routine as a valid angiographic parameter of viability?

The success rate of percutaneous coronary artery intervention (PCI) of chronic total occlusion (CTO) lesions have increased in the recent years. However, improvement of function is only possible when significant myocardial viability is present. One of the most important factors of maintaining myocardial viability is the opening and development of collaterals. Our hypothesis was that with a higher degree of collaterals more viable myocardium is present. In 38 patients we compared the degree of collaterals, evaluated with a conventional coronary angiogram (CCA) and graded by the Rentrop classification to transmural extent of the scar obtained in a viability study with magnetic resonance (MRI). We found a statistically significant association of the degree of collaterals determined with Rentrop method and transmural extent of the scar as measured by CMR (p = 0.001; Tau = -0.144). Additionally, associations showed an increase in the ratio between viable vs. non-viable myocardium with the degree of collaterals. Our study suggests that it may be beneficial to routinely grade the collaterals at angiography in patients with CTO as an assessment of myocardial viability.

Relationship between quality of coronary collateral and myocardial viability in chronic total occlusion: a magnetic resonance study.

Revascularization of chronic total occlusion (CTO) is still debated regarding its indications and therapeutic benefits. Guidelines recommend patient selection based on ischemia detection and viability assessment. We aimed to investigate the relationship between the quality of coronary collaterals (CC), graded by Rentrop classification, and myocardial viability assessed by cardiovascular magnetic resonance (CMR). Unselected 100 consecutive patients with a single CTO were prospectively enrolled. CC of Rentrop grade two or three were considered as well-developed. Analyzing late gadolinium enhancement (LGE) images, CTO territories with mean segmental transmural scar extent < 50% were considered viable. Of the 100 patients (70 male, mean age 58.0 ± 6 years), 73 patients (73%) had angiographically visible CC. Based on LGE, patients were classified into viable (n = 50) and non-viable (n = 50) groups. Significant differences between both groups existed regarding frequency of diabetes mellitus (p = 0.044), frequency of congestive heart failure (p = 0.032), presence of pathological Q in CTO territory (p = 0.039); and presence of well-developed CC (p < 0.001). Binary logistic regression and receiver operating characteristic curve showed that presence of well-developed CC could independently (OR 9.4, 95% CI: 2.6-33.6, p < 0.001) predict myocardial viability with a sensitivity and a specificity of 72% and 74%, respectively (AUC: 0.796, 95% CI: 0.708-0.884, P < 0.001). The presence of well-developed CC could independently predict with high accuracy myocardial viability assessed by LGE in territories subtended by CTO vessels. Therefore, search for viable myocardium using different imaging modalities, e.g. CMR, may be recommended in CTO patients with well-developed CC.

Assessing the influence of atherosclerosis on drug coated balloon therapy using computational modelling.

Interventional therapies such as drug-eluting stents (DES) and drug-coated balloons (DCB) have significantly improved the clinical outcomes of patients with coronary occlusions in recent years. Despite this marked improvement, ischemic cardiovascular disease remains the most common cause of death worldwide. To address this, research efforts are focused on improving the safety and efficacy of the next generation of these devices. However, current experimental methods are unable to account for the influence of atherosclerotic lesions on drug uptake and retention. Therefore, in this study, we used an integrated approach utilizing both in vitro and in silico methods to assess the performance of DCB therapy. This approach was validated against existing in vivo results before being used to numerically estimate the effect of the atheroma. A bolus release of sirolimus was observed with our coating matrix. This, coupled with the rapid saturation of specific and non-specific binding sites observed in our study, indicated that increasing the therapeutic dose coated onto the balloons might not necessarily result in greater uptake and/or retention. Additionally, our findings alluded to an optimal exposure time, dependent on the coating matrix, for the DCBs to be expanded against the vessel. Moreover, our findings suggest that a biphasic drug release profile might be beneficial for establishing and maintaining the saturation of bindings sites within severely occluded vessels. Ultimately, we have demonstrated that computational methods may be capable of assessing the efficacy of DCB therapy as well as predict the influence of atherosclerotic lesions on said efficacy.

Fate of lumen size in distal coronary segment following successful chronic total occlusion recanalization.

BACKGROUND: Restoration of anterograde blood flow leads to alterations in vascular wall stress that may influence lumen size distal to chronic total occlusion (CTO) lesions. We sought to assess changes in lumen diameter of segments distal to the stent segment of successfully recanalized CTO. METHODS: We analyzed 507 consecutive CTO cases with stent implantation that underwent follow-up angiography at a single high-volume center (mean follow-up of 13.5 months). Segments ≤40 mm distal to the stent edge were analyzed using quantitative coronary angiography. RESULTS: At follow-up, lumen diameters significantly increased; diameter changes of 0.26 ± 0.47 (percent diameter change of 18.2%) at 5 mm distal, mean lumen diameter changes of 0.23 ± 0.35 (14.3%) and minimal lumen diameter changes of 0.22 ± 0.80 (24.7%) (all p < 0.001). Lumen enlargement was similar between visually shrunken and stenosed vessels (degree of stenosis ≥20% with luminal irregularities) distal to stents; 5 mm distal (0.32 ± 0.48 vs. 0.30 ± 0.48, p = 0.76), mean lumen diameter changes (0.26 ± 0.37mm vs. 0.26±0.33 mm, p = 0.94), minimal lumen diameter changes (0.28 ± 0.43 mm vs. 0.22 ± 1.30 mm, p = 0.48). There was no association between degree of in-stent narrowing and changes in distal lumen diameter (Spearman r = -0.02, p = 0.59). Multivariate logistic regression for the predictors of greater lumen enlargement indicated that patients with left ventricle dysfunction (ejection fraction ≤45%) had greater enlargement [odds ratio (OR): 2.53, 95% confidence interval (CI): 1.23-5.23, p = 0.01]. Conversely, a low hematocrit (male <40%, and female <35%) was associated with attenuated lumen enlargement (OR: 0.68 95% CI: 0.47-0.98; p = 0.04). CONCLUSIONS: Lumen diameter distal to CTO lesions significantly increased following successful revascularization, regardless of diseased status of the distal bed or degree of in-stent narrowing. These findings implicate appropriate determination of stent size, stent coverage length, as well as management strategies of distal vessels.

Two females with coronary artery occlusion caused by presumed Kawasaki disease would have delivered without recognition of ischaemic heart disease.

We report two females with coronary artery occlusion caused by presumed Kawasaki disease that delivered children without any special treatment. After a 58-year-old female had ventricular tachycardia, a giant coronary artery aneurysm with calcification at the bifurcation of the left coronary artery and segmental stenosis of the right coronary artery were pointed out by CT angiography. She had an episode of sepsis when 3 years old. Further, she remembered chest pain during sleep after that episode. She had delivered twice without any complication during her 20s. Her diagnosis was undiagnosed coronary artery lesions caused by presumed Kawasaki disease and a previous myocardial infarction, and she underwent radiofrequency catheter ablation and implantable cardioverter defibrillator implantation. The other 48-year-old female was accidentally discovered to have coronary artery calcification on CT, while experiencing pneumonia. Her CT angiograms revealed a right coronary artery occlusion and coronary artery calcification at segments 1, 6, and 11. She had a history of "scarlet fever" before 12 months. Premature ventricular contractions were detected, while delivering her first child when 31 years old. However, she was not diagnosed as ischaemic heart disease and delivered twice by a vaginal delivery without any complication. Current guidelines recommend systemic anti-coagulation and anti-platelet therapy for all patients with giant aneurysms resulting from Kawasaki disease in childhood. The two women reported here were fortunate not to have had complications during pregnancy and delivery despite their severe coronary artery aneurysms, which were unrecognised clinically until later in life. They were lucky cases.

Connexin 43 Deficiency Is Associated with Reduced Myocardial Scar Size and Attenuated TGFß1 Signaling after Transient Coronary Occlusion in Conditional Knock-Out Mice.

Previous studies demonstrated a reduction in myocardial scar size in heterozygous Cx43+/- mice subjected to permanent coronary occlusion. However, patients presenting with ST segment elevation myocardial infarction often undergo rapid coronary revascularization leading to prompt restoration of coronary flow. Therefore, we aimed to assess changes in scar size and left ventricular remodeling following transient myocardial ischemia (45 min) followed by 14 days of reperfusion using Cx43fl/fl (controls) and Cx43Cre-ER(T)/fl inducible knock-out (Cx43 content: 50%) mice treated with vehicle or 4-hydroxytamoxifen (4-OHT) to induce a Cre-ER(T)-mediated global deletion of the Cx43 floxed allele. The scar area (picrosirius red), measured 14 days after transient coronary occlusion, was similarly reduced in both vehicle and 4-OHT-treated Cx43Cre-ER(T)/fl mice, compared to Cx43fl/fl animals, having normal Cx43 levels (15.78% ± 3.42% and 16.54% ± 2.31% vs. 25.40% ± 3.14% and 22.43% ± 3.88% in vehicle and 4-OHT-treated mice, respectively, p = 0.027). Left ventricular dilatation was significantly attenuated in both Cx43-deficient groups (p = 0.037 for left ventricular end-diastolic diameter). These protective effects were correlated with an attenuated enhancement in pro-transforming growth factor beta 1 (TGFß1) expression after reperfusion. In conclusion, our data demonstrate that Cx43 deficiency induces a protective effect on scar formation after transient coronary occlusion in mice, an effect associated with reduced left ventricular remodeling and attenuated enhancement in pro-TGFß1 expression.

Relationship of a thinned medial layer to the attenuated contractile response in atherosclerotic coronary arteries.

Coronary arteries with advanced atherosclerosis do not necessarily have greater contractile responses than those with early atherosclerosis. This study aimed to clarify the relationship between thickness of the medial layer and the contractile response to acetylcholine (ACh) in coronary artery using optical coherence tomography (OCT). The OCT and the vasomotor response to ACh in the left anterior descending coronary artery were assessed in 32 patients with previous myocardial infarction. The intimal and medial layer areas were measured by planimetric analysis of the OCT images. The coronary contractile response to ACh had a positive linear relationship with medial area (r = 0.61, P < 0.001). In contrast, the relationship between the coronary contractile response to ACh and intimal area was described by an inverted U-shaped curve that was fitted to a quadratic regression model (R2 = 0.35, P = 0.002, y-axis, contraction; x-axis, intimal area). The contractile response increased as the intimal layer thickened up to the inflection point; thereafter, the contractile response declined. The relationship between medial area and intimal area was also described by an inverted U-shaped curve that was fitted to a quadratic regression model (R2 = 0.41, P < 0.01, y-axis, medial area; x-axis, intimal area). The medial area increased as the intimal area thickened up to the inflection point; thereafter, the medial area thinned. In conclusion, the thinned medial layer was associated with the attenuated contractile response in a coronary artery with greater atherosclerosis.NEW & NOTEWORTHY This is the first clinical study to show the relationship between the contractile response and the thickness of medial smooth muscle layer in coronary artery of patients with previous myocardial infarction using OCT. The contractile response to acetylcholine was attenuated, and medial layer area was thinned in coronary artery with greater atherosclerosis compared with those in coronary artery with mild or moderate atherosclerosis. The coronary contractile response was positively correlated with thickness of the medial layer in coronary arteries with either mild or greater atherosclerosis. Thus, coronary arteries with advanced atherosclerosis do not necessarily have greater contractile responses than those with early atherosclerosis, which could be related to the thinned medial layer.