Circ_005077 accelerates myocardial lipotoxicity induced by high-fat diet via CyPA/p47PHOX mediated ferroptosis.

The long-term high-fat diet (HFD) can cause myocardial lipotoxicity, which is characterized pathologically by myocardial hypertrophy, fibrosis, and remodeling and clinically by cardiac dysfunction and heart failure in patients with obesity and diabetes. Circular RNAs (circRNAs), a novel class of noncoding RNA characterized by a ring formation through covalent bonds, play a critical role in various cardiovascular diseases. However, few studies have been conducted to investigate the role and mechanism of circRNA in myocardial lipotoxicity. Here, we found that circ_005077, formed by exon 2-4 of Crmp1, was significantly upregulated in the myocardium of an HFD-fed rat. Furthermore, we identified circ_005077 as a novel ferroptosis-related regulator that plays a role in palmitic acid (PA) and HFD-induced myocardial lipotoxicity in vitro and in vivo. Mechanically, circ_005077 interacted with Cyclophilin A (CyPA) and inhibited its degradation via the ubiquitination proteasome system (UBS), thus promoting the interaction between CyPA and p47phox to enhance the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase responsible for ROS generation, subsequently inducing ferroptosis. Therefore, our results provide new insights into the mechanisms of myocardial lipotoxicity, potentially leading to the identification of a novel therapeutic target for the treatment of myocardial lipotoxicity in the future.

miR-141-3p regulates saturated fatty acid-induced cardiomyocyte apoptosis through Notch1/PTEN/AKT pathway via targeting PSEN1.

It has been reported that miR-141-3p levels are markedly upregulated in the cardiomyocytes of obese rats induced by a high-fat diet. However, the role of miR-141-3p in myocardial lipotoxicity remains elusive. In the present study, the role of miR-141-3p in lipotoxic injury of H9c2 cells induced by palmitic acid (PA) and its possible mechanisms were assessed. The results indicated that miR-141-3p was significantly upregulated in PA-induced cardiomyocytes. miR-141-3p inhibitor enhanced the cell viability, reduced the release of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and troponin I (CTN-I), decreased cell apoptosis rate, and repressed the activation of mitochondrial apoptosis pathway in PA-treated H9c2, whereas treatment with miR-141-3p mimics resulted in the opposite effects. Mechanistically, it was further revealed that miR-141-3p could specifically bind to presenilin 1 (PSEN1) 3'UTR, and upregulating miR-141-3p levels reduced the expression of PSEN1, thereby inhibiting the activation of the Notch1/PTEN/AKT pathway. Additionally, inhibition of Notch1/AKT signaling pathway by its inhibitor could abrogate the effect of miR-141-3p on mitochondrial-mediated apoptosis induced by PA. In conclusion, the present study demonstrates that miR-141-3p regulates saturated fatty acid-induced cardiomyocyte apoptosis through Notch1/PTEN/AKT pathway via targeting PSEN1, which gains a new insight into the mechanisms of myocardial lipotoxic injury.

Clinical characteristics of cardiovascular patients with extremely low levels of high-density lipoprotein cholesterol.

BACKGROUND: Extremely low levels of high-density lipoprotein cholesterol (HDL-C) are related to high cardiovascular mortality. The underlying mechanism is not well known. This research aims to study the clinical characteristics of cardiovascular patients with extremely low levels of HDL-C. METHODS: All cardiovascular patients in a single Chinese cardiology center that were admitted from January to December 2019 were reviewed. The clinical characteristics of those with HDL-C<20 mg/dL were investigated. RESULTS: A total of 20,655 individuals were enrolled. Of these, 52.17 % were males, and the average age was 58.20 ± 12.98 years old. The prevalence of HDL-C<20 mg/dL was 0.47 % for all patients (N=98) and 1.05 % for inpatients. Of those with HDL-C<20 mg/dL, 88.8 % were inpatients, and 77.6 % were males. Their average age was 60.7 ± 15.1 years. Compared with matched patients with normal HDL-C, systemic inflammation (OR= 5.556, 95% CI 2.798-11.030), hypoalbuminemia (OR=5.714, 95% CI 2.702-12.085), hyperuricemia (OR=5.156, 95% CI 2.560-10.386), low T3 syndrome (OR=4.278, 95% CI 1.627-11.245), anemia (OR=3.577, 95% CI 1.680-7.617), diabetes (OR=3.534, 95% CI 1.693-7.376) and hypertriglyceridemia (OR=2.493, 95% CI 1.264-4.918) were identified as adverse concomitant factors of extremely low HDL-C. HDL-C levels were inversely correlated with the total risk scores in patients with HDL-C<20 mg/dL (r=-0.381, P<0.001) and more significantly correlated in patients with HDL-C<15 mg/dL (r=-0.511, P=0.004). CONCLUSIONS: Extremely low levels of HDL-C tend to occur more frequently in males, older individuals and inpatients. For cardiovascular patients, extremely low levels of HDL-C are usually due to the presence of multiple adverse factors with relatively severe conditions. This could explain the high cardiovascular mortality of individuals with extremely low levels of HDL-C.

Incremental value of three-dimensional echocardiography for evaluating left atrial function in patients with coronary slow flow phenomenon: a case control study.

BACKGROUND: Coronary slow flow phenomenon (CSFP) involves the delayed opacification of the coronary distal vessel, in the absence of an obstructive lesion in the epicardial coronary artery during angiography. Since the link between left atrial (LA) function and decreased left ventricular function is still unclear, we evaluated LA function using real-time three-dimensional echocardiography (RT3DE) in patients with CSFP, and subsequently determined the incremental value of RT3DE. METHODS: This study enrolled 60 patients with CSFP and 45 control subjects. CSFP was diagnosed based on thrombolysis in myocardial infarction frame count (TFC). The LA phasic volume and function was evaluated by both two-dimensional echocardiography (2DE) and RT3DE. RESULTS: The LA maximal volume (Volmax), pre-systolic volume (Volp), and minimal volume (Volmin) increased, but LA total and active ejection fraction decreased in patients with CSFP. Based on our results, Volmax, Volp, Volmin, and LA total and active ejection fraction correlated with TFC, and with the number of arteries involved. The LA total ejection fraction by RT3DE was the only independent predictor for CSFP (odds ratio, 0.64 [95% confidence interval, 0.49-0.83]; P = 0.001). Also, the LA total ejection fraction by RT3DE demonstrated good predictive power for CSFP, with a cut-off value of 54.15% (area under curve, 0.85; sensitivity, 84%; specificity, 83%). CONCLUSIONS: The LA reservoir and contractile function decreased in the patients with CSFP and correlated with coronary flow rate and with the number of arteries involved. The LA total ejection fraction by RT3DE can independently predict CSFP, and RT3DE demonstrated incremental value for evaluating LA phasic function in the patients with CSFP compared to 2DE.

Down-regulation of GAS5 ameliorates myocardial ischaemia/reperfusion injury via the miR-335/ROCK1/AKT/GSK-3ß axis.

Growth arrest-specific transcript 5 (GAS5), along non-coding RNA (LncRNA), is highly expressed in hypoxia/reoxygenation (H/R)-cardiomyocytes and promotes H/R-induced apoptosis. In this study, we determined whether down-regulation of GAS5 ameliorates myocardial ischaemia/reperfusion (I/R) injury and further explored its mechanism. GAS5 expression in cardiomyocytes and rats was knockdown by transfected or injected with GAS5-specific small interfering RNA or adeno-associated virus delivering small hairpin RNAs, respectively. The effects of GAS5 knockdown on myocardial I/R injury were detected by CCK-8, myocardial enzyme test, flow cytometry, TTC and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining. qRT-PCR and luciferase reporter assay were carried out to analyse the relationship between GAS5 and miR-335. The regulation of GAS5 on Rho-associated protein kinase 1 (ROCK1) expression, the activation of PI3K/AKT/GSK-3ß pathway and mitochondrial permeability transition pore (mPTP) opening was further evaluated. The results indicated that GAS5 knockdown enhanced the viability, decreased apoptosis and reduced the levels of lactate dehydrogenase and creatine kinase-MB in H/R-treatment cardiomyocytes. Meanwhile, down-regulation of GAS5 limited myocardial infarct size and reduced apoptosis in I/R-heart. GAS5 was found to bind to miR-335 and displayed a reciprocal inhibition between them. Furthermore, GAS5 knockdown repressed ROCK1 expression, activated PI3K/AKT, thereby leading to inhibition of GSK-3ß and mPTP opening. These suppressions were abrogated by miR-335 inhibitor treatment. Taken together, our results demonstrated that down-regulation of GAS5 ameliorates myocardial I/R injury via the miR-335/ROCK1/AKT/GSK-3ß axis. Our findings suggested that GAS5 may be a new therapeutic target for the prevention of myocardial I/R injury.

HDL-C to hsCRP ratio is associated with left ventricular diastolic function in absence of significant coronary atherosclerosis.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) is considered as a protective marker of coronary atherosclerotic disease (CAD). It is still not clear if HDL-C is associated with left ventricular (LV) diastolic function in an inflammation-related manner in absence of significant coronary atherosclerosis. METHODS: 392 patients who complained of chest pain and were suspected of CAD without heart failure were enrolled in this study. Coronary angiography or coronary artery CT scan was performed to detect coronary atherosclerosis. Transthoracic echocardiography was performed to evaluate cardiac function. Plasma level of HDL-C and high-sensitive C-reactive protein (hsCRP) were determined in each subject. Relationship between HDL-C/hsCRP ratio and LV diastolic function in subjects without significant coronary atherosclerosis was investigated. RESULTS: 204 subjects without significant coronary plaques were analyzed finally, including 84 males and 120 females whose ages ranged from 30 to 84 years old. When divided into HDL-C/hsCRP quartiles, those in the fourth quartile demonstrated the best diastolic function (E/e' 10.14 ± 2.87, P = 0.02 ). HDL-C/hsCRP was the most significant factor correlated with E/e' in univariate regression analysis (r = - 0.232, P < 0.001) and multiple regression analysis adjusted by other factors (standardized ß = - 0.258 , P < 0.0005 ). In logistic regression, HDL-C/hsCRP was proved to be a protective factor of LV diastolic dysfunction E/e' > 14 (OR = 0.649, 95%CI 0.444-0.948,P = 0.025 ). The sensitivity and specificity of using HDL-C/hsCRP < 0.98 to predict LV diastolic dysfunction were 64.3% and 56.2%, respectively. HDL-C/hsCRP ratio presented a reduced trend as increasing rate of CV risk factors. CONCLUSIONS: HDL-C/hsCRP ratio strongly correlates with LV diastolic function in absence of significant coronary atherosclerosis. Low HDL-C/hsCRP ratio tends to relate with LV diastolic dysfunction.

Left ventricular systolic dysfunction potentially contributes to the symptoms in heart failure with preserved ejection fraction.

AIMS: Left ventricular diastolic dysfunction (LVDD) is considered a key factor associated with heart failure (HF) symptoms in patients with preserved ejection fraction (HFpEF). However, LV systolic performance, including LV systolic function and synchrony, has not been well characterized in these patients. The aims of this study were to assess to investigate the underlying relationship and differences between subclinical LVDD and HFpEF. METHODS: Eighty-six patients with LVDD were recruited (58 with HFpEF and 28 with subclinical LVDD). Systolic left ventricular (LV) longitudinal strain (LS), systolic longitudinal strain rate (LSrS), early diastolic longitudinal strain rate (LSrE), and late diastolic longitudinal strain rate (LSrA) were measured using speckle tracking echocardiography. LV diastolic and systolic dyssynchrony (Te-SD and Ts-SD) were calculated. Forty age- and sex-matched healthy individuals were enrolled as a control group. RESULTS: LV global LS and LSrS were decreased in patients with HFpEF than in normal controls and subclinical LVDD patients (P < .05). Te-SD and Ts-SD were significantly more prolonged in subclinical LVDD and HFpEF patients than in the control group (P < .05). Reduced LS was associated with HF symptoms in LVDD patients, and a cutoff value of -18% for LS could differentiate HFpEF from subclinical LVDD with 73% sensitivity and 69% specificity. CONCLUSION: LV systolic function and mechanical dyssynchrony were impaired in HFpEF patients. Deteriorated LV longitudinal systolic function was likely correlated with the symptoms of HFpEF.

Association between increased serum alkaline phosphatase and the coronary slow flow phenomenon.

BACKGROUND: Despite marked advances in our understanding of the pathophysiology of the coronary slow flow phenomenon (CSFP), the exact mechanism remains unclear. Previous studies have suggested that CSFP might be associated with generalized atherosclerosis, endothelial dysfunction, and low-grade chronic inflammation. High serum alkaline phosphatase (ALP) levels are associated with vascular calcification, atherosclerotic disease, and an increased risk of cardiovascular events. However, the relationship between ALP and CSFP is unclear. METHODS: We investigated 64 patients with angiographically proven CSFP and 50 with normal coronary flow. Serum ALP levels were measured in all studied individuals. RESULTS: Serum ALP levels in patients with CSFP were significantly higher than those in the control group (70.5 ± 17.1 vs. 61.9 ± 16.1 U/L, P = 0.007). A positive association was observed (r = 0.42, P = 0.032) between serum ALP levels and the mean thrombolysis in myocardial infarction frame count (mTFC). Regression analysis showed a high serum ALP level was the only independent predictor of the mTFC (ß = 0.309, P < 0.001). Moreover, our study showed that a serum ALP level > 67.5 U/L was a predictor of CSFP (sensitivity = 83.3%, specificity = 84.1%). CONCLUSIONS: Patients with CSFP show high serum ALP levels, which may be associated with the pathogenesis of CSFP. A high serum ALP level is a predictor of CSFP. Future studies are needed to clarify the role of ALP in patients with CSFP.

Left ventricular diastolic and systolic dyssynchrony and dysfunction in heart failure with preserved ejection fraction and a narrow QRS complex.

Aims: Mechanical dyssynchrony has been reported in heart failure with preserved ejection fraction (HFpEF), with a majority of patients having a narrow QRS complex; however, whether any benefit is observed with restoration of dyssynchrony remains unclear. We sought to assess left ventricular (LV) dyssynchrony and function in HFpEF and elucidate the underlying mechanisms that may account for HFpEF. Methods: Seventy-eighty patients with a narrow QRS complex including 47 with HFpEF, 31 with heart failure with reduced ejection fraction (HFrEF) patients, and 29 with asymptomatic left ventricular diastolic dysfunction (LVDD) were recruited. Forty-five normal subjects acted as controls. Systolic LV longitudinal strain (LS), systolic longitudinal strain rate (LSrS), early diastolic longitudinal strain rate (LSrE), and late diastolic longitudinal strain rate (LSrA) were measured using speckle tracking echocardiography. LV diastolic and systolic dyssynchrony (Te-SD and Ts-SD) were calculated. Results: Te-SD and Ts-SD were prolonged in HFpEF and HFrEF patients than in the control group (p<0.05). However, Ts-SD was shorter in HFpEF patients compared to HFrEF patients despite a narrow QRS complex (p<0.05). LV global LS, LSrS, and LSrE were decreased in patients with HFpEF and HFrEF compared to other groups, with HFrEF being even more reduced than HFpEF (p<0.05). Reduced LS, LSrS, and LSrE could effectively differentiate HF from asymptomatic LVDD patients (p<0.05). Conclusion: HFrEF exhibited increased systolic dyssynchrony compared to HFpEF despite a narrow QRS complex in addition to the more reduced diastolic and systolic function. Therefore, targeting to improve diastolic and systolic function instead of managing systolic dyssynchrony might be of great importance in the treatment of HFpEF.

Evaluation of Plasma Thrombomodulin in Patients with Coronary Slow Flow.

BACKGROUND: It has been reported that coronary slow flow (CSF) is associated with acute myocardial infarction, ventricular tachycardia, ventricular fibrillation, and even sudden cardiac death. Although studies concerning the etiopathogenesis of CSF are scarce, diffuse atherosclerosis and endothelial dysfunction are thought to play important roles. It has been suggested that a high plasma thrombomodulin (TM) level seems to play an important role in the pathogenesis of atherosclerosis and endothelial dysfunction. OBJECTIVES: We hypothesized that a high plasma TM level might be associated with CSF and aimed to research the relationship between plasma TM level and CSF. METHODS: Fifty-two CSF patients with angiographically proven CSF and 44 cases with normal coronary flow were included in this study. Coronary flow velocity was determined by the thrombolysis in myocardial infarction (TIMI) frame count method. Plasma TM levels were measured in all the study subjects. RESULTS: Plasma TM levels were significantly higher in the CSF group compared to the control group (3.9 ± 0.5 vs. 3.6 ± 0.3 ng/mL, p = 0.01). There was a positive relationship (r = 0.31, p = 0.002) between plasma TM level and mean TIMI frame count (TFC). Factors associated with mean TFC were plasma TM level (ß = 0.206, p = 0.038) and red cell distribution width (ß = 0.088, p = 0.009) in multiple linear regression analysis. CONCLUSIONS: Patients with CSF have a higher plasma TM level, and this may play an important role in the pathogenesis of CSF. An elevated plasma TM level may be a predictor of CSF. Future studies are needed to confirm these results.

Assessment of risk factors and left ventricular function in patients with slow coronary flow.

Slow coronary flow (SCF) is characterized by delayed distal vessel opacification in the absence of significant epicardial coronary disease. Life-threatening arrhythmias and sudden cardiac death can occur; however, the pathological mechanism and influence on left ventricular function remain undetermined. We aimed to assess the risk factors and left ventricular (LV) function in SCF and evaluate the relationships between thrombolysis in myocardial infarction frame count (TFC) and the number of involved coronary arteries with LV function in patients with SCF. We included 124 patients who underwent coronary angiography because of symptoms of angina; 71 patients with angiographically proven SCF and 53 cases with normal coronary flow pattern. SCF was diagnosed as TFC >27 in at least one coronary artery. Complete blood count and biochemical parameters were compared between the two groups. Conventional echocardiography and tissue Doppler imaging were used to assess LV systolic and diastolic function. Platelet aggregation rate induced by ADP was an independent predictor of SCF and positively correlated with coronary artery mean TFC (mTFC) (r = 0.514, P < 0.001) and the number of coronary arteries with SCF (r = 0.628, P < 0.001). Early diastolic mitral inflow velocity (E) (0.66 ± 0.15 vs. 0.74 ± 0.17, P = 0.008), ratio of early to late diastolic mitral inflow velocity (E/A) (0.95 ± 0.29 vs. 1.15 ± 0.35, P = 0.002), global myocardial peak early diastolic velocity (gVe) (4.41 ± 1.25 vs. 4.96 ± 1.45, P = 0.037), and ratio of global myocardial peak early to late diastolic velocity (gVe/gVa: 1.09 ± 0.45 vs. 1.36 ± 0.58, P = 0.006) were decreased in patients with SCF compared with controls. gVe (3 vs. 0 branches, 4.08 ± 1.14 vs. 4.97 ± 1.45, respectively, P = 0.008) deteriorated significantly in patients with SCF involving three coronary arteries. mTFC negatively correlated with E and E/A (r = -0.22, P = 0.02; r = -0.20, P = 0.04, respectively). The number of coronary arteries with SCF negatively correlated with E, E/A, gVe and gVe/gVa (r = -0.23, P = 0.02; r = -0.25, P = 0.009; r = -0.25, P = 0.008; r = -0.21, P = 0.03, respectively). Platelet aggregation rate induced by ADP was an independent predictor of SCF and positively correlated with coronary artery TFC and the number of affected coronary arteries. Left ventricular global and regional diastolic function was impaired in SCF patients. Furthermore, the number of coronary arteries involved rather than coronary artery TFC determined the severity of left ventricular dysfunction in patients with SCF.

Hypercholesterolemia abrogates the protective effect of ischemic postconditioning by induction of apoptosis and impairment of activation of reperfusion injury salvage kinase pathway.

Ischemic postcontioning (IPoC) is an effective method to prevent myocardial ischemia reperfusion injury (MIRI), but its cardioprotection is usually blocked in the presence of hypercholesterolemia (HC) and the potential mechanism is still unknown. In this study, we investigated the roles of reperfusion injury salvage kinase (RISK) and apoptosis-related pathways in the attenuation of cardioprotection of IPoC in the presence of HC. The results showed that IPoC significantly decreased the infarct size and apoptosis, improved the recovery of ischemic myocardium, but these beneficial effects were reversed by high cholesterol diet-induced HC. Moreover, we also found that HC inhibited the phosphorylation of Akt and ERK1/2 which usually activated by IPoC in normal heart, induced excessive apoptosis by down-regulating Bcl-2 and up-regulating Bax, cytochrome c, caspase 9 and caspase 3 when compared with that in normal heart. Taken together, our results demonstrated that the cardioprotection of IPoC was abolished by HC, which was associated with inactivation of RISK signal pathway and dysregulation of downstream apoptosis-related pathway.

WITHDRAWN: Hypercholesterolemia aggravates myocardial ischemia reperfusion injury via activating endoplasmic reticulum stress-mediated apoptosis.

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Hypercholesterolemia aggravates myocardial ischemia reperfusion injury via activating endoplasmic reticulum stress-mediated apoptosis.

The effect of hypercholesterolemia on myocardial ischemia reperfusion injury (MIRI) is in controversy and the underlying mechanism is still not well understood. In the present study, we firstly detected the effects of hypercholesterolemia on MIRI and the role of endoplasmic reticulum (ER) stress-mediated apoptosis pathway in this process. The infarct size was determined by TTC staining, and apoptosis was measured by the TUNEL method. The marker proteins of ER stress response and ER stress-mediated apoptosis pathway were detected by Western blot. The results showed that high cholesterol diet-induced hypercholesterolemia significantly increased the myocardial infarct size, the release of myocardium enzyme and the ratio of apoptosis, but did not affect the recovery of cardiac function. Moreover, hypercholesterolemia also remarkably up-regulated the expressions of ER stress markers (glucose-regulated protein 78 and calreticulin) and critical molecules in ER stress-mediated apoptosis pathway (CHOP, caspase 12, phospho-JNK). In conclusion, our study demonstrated that hypercholesterolemia enhanced myocardial vulnerability/sensitivity to ischemia reperfusion injury involved in aggravation the ER stress and activation of ER stress-mediated apoptosis pathway and it gave us a new insight into the underlying mechanisms associated with hypercholesterolemia-induced exaggerated MIRI and also provided a novel target for preventing MIRI in the presence of hypercholesterolemia.

[Clinical values of ST-segment changes in ST-segment elevated myocardial infarction patients within 24 hours post primary percutaneous coronary interventions].

OBJECTIVE: To explore the clinical values of ST-segment changes in ST-segment elevated myocardial infarction (STEMI) patients within 24 hours after primary percutaneous coronary intervention (PCI). METHODS: A total of 225 patients with STEMI underwent primary PCI were enrolled, the ST segment resolution 1 hour after PCI was calculated and the patients were divided into group A (n = 135, Sgr;STE resolved ≥ 50%) and group B (n = 90, Sgr;STE resolved < 50%). The patients in group B were further divided into group C (n = 56, Sgr;STE resolved ≥ 50%) and group D (n = 34, Sgr;STE resolved < 50%) according to the ST segment resolution at 24 hours after PCI. TIMI flow after PCI, in-hospital major adverse cardiac events (MACE) and cardiac function about 7 days post PCI were analyzed. RESULTS: Data between group A and group B were similar except the incidence of pre-PCI Killip ≥ II was significantly higher in group B than in group A (37.8% (34/90) vs. 17.0% (23/135), P < 0.05). Incidence of complicated diabetes (P < 0.05), pre-PCI Killip ≥ II (55.9% (19/34) vs. 26.8% (15/56), P < 0.05) and multivessel disease (70.6% (24/34) vs. 35.7% (20/56), P < 0.05) were significantly higher in group D than in group C. TIMI 3 and the opening time of IRA was similar between group A and group B and between group C and group D. The incidence of in-hospital MACE was significantly higher in group B than in group A (14.4% (13/90) vs. 3.0% (4/135), P < 0.05) which was similar between group C and group D. CONCLUSION: Early (1 hour) but not late (24 hours) ST resolution post PCI is related to a favorable clinical outcome in STEMI patients.

Cardioprotective effects of low-dose combination therapy with rosuvastatin and fasudil in the isolated rat heart.

The cardiovascular pleiotropic effects of statins and a Rho-kinase inhibitor (fasudil) could be of interest to prevent myocardial ischemia reperfusion injury (MIRI). In the present study, we investigated whether low-dose rosuvastatin and fasudil, separately not possessing cardioprotection, express cardioprotective effects when combined. The isolated rat hearts underwent 30 min global ischemia and 120 min reperfusion. Rosuvastatin (3 microM) and fasudil (1 microM) were administered 15 min before ischemia. NG-nitro-L-arginine methylester (30 microM) (L-NAME) was given at the onset of reperfusion. Myocardial infarct size, apoptosis, myocardial nitric oxide (NO) content and endothelial nitric oxide synthase (eNOS) expression were evaluated. The combination treatment significantly decreased infarct size and percentage of apoptosis and increased the content of NO and eNOS expression, whereas treatment with rosuvastatin and fasudil alone at the same doses did not lead to cardioprotection. Furthermore, L-NAME reversed the cardioprotective effect of rosuvastatin/fasudil combination treatment. In summary, rosuvastatin combined with fasudil treatment had synergistic protective effects against MIRI, which were mediated by increasing eNOS and NO production. This new concept could be valuable in MIRI prevention.

Understanding the pathogenesis of coronary slow flow: Recent advances.

Coronary slow flow is taken to be indicative of delayed filling of terminal vessels of the coronary arteries in the absence of coronary stenosis, as detected using coronary angiography. Patients suffering from coronary slow flow typically experience recurrent chest pain, thereby markedly affecting their quality of life. The etiology and pathogenesis of coronary slow flow, which is gradually attracting clinical attention, have yet to be sufficiently established, although it is currently believed that they may be associated with endothelial dysfunction in the coronary arteries, inflammatory response, abnormalities in microvascular reserve function, subclinical atherosclerosis, blood cell and platelet abnormalities, and genetic factors. In this review, we provide a brief overview of recent progress in research on the pathogenesis of coronary slow flow with a view toward elucidating the possible underlying pathogenesis and identify targets and directions for the treatment of this condition.

Usefulness of soluble endothelial protein C receptor combined with left ventricular global longitudinal strain for predicting slow coronary flow: A case-control study.

BACKGROUND: Slow coronary flow (SCF) is an angiographic entity characterized by delayed coronary opacification without an evident obstructive lesion in the epicardial coronary artery. However, patients with SCF have decreased left ventricular (LV) global longitudinal strain (GLS). SCF is associated with inflammation, and soluble endothelial protein C receptor (sEPCR) is a potential biomarker of inflammation. Therefore, under evaluation herein, was the relationship between SCF and sEPCR and the predictive value of sEPCR and LV GLS for SCF was investigated. METHODS: Twenty-eight patients with SCF and 34 controls were enrolled. SCF was diagnosed by the thrombolysis in myocardial infarction frame count (TFC). The plasma level of sEPCR was quantified using enzyme-linked immunosorbent assay. LV GLS was measured by two-dimensional speckle-tracking echocardiography. RESULTS: Plasma sEPCR was significantly higher in patients with SCF than in controls and was positively correlated with the mean TFC (r = 0.67, p < 0.001) and number of involved vessels (r = 0.61, p < 0.001). LV GLS was decreased in patients with SCF compared to that in controls. sEPCR level (OR = 3.14, 95% CI 1.55-6.36, p = 0.001) and LV GLS (OR = 1.44, 95% CI 1.02-2.04, p = 0.04) were independent predictors of SCF. sEPCR predicted SCF (area under curve [AUC]: 0.83); however, sEPCR > 9.63 ng/mL combined with LV GLS > -14.36% demonstrated better predictive power (AUC: 0.89; sensitivity: 75%; specificity: 91%). CONCLUSIONS: Patients with SCF have increased plasma sEPCR and decreased LV GLS. sEPCR may be a useful potential biomarker for SCF, and sEPCR combined with LV GLS can better predict SCF.

Incremental Value of Three-dimensional Speckle-tracking Echocardiography for Evaluating Left Ventricular Systolic Function in Patients with Coronary Slow Flow.

The purpose was to evaluate left ventricular (LV) systolic function in patients with coronary slow flow (CSF), and compared the incremental values of 3-dimensional (3D) speckle-tracking echocardiography (STE). Seventy-three patients with CSF and 60 control subjects were enrolled. CSF was diagnosed during coronary angiography. Two-dimensional (2D) and 3D global strain were measured using STE. Sex, mitral E, 2D GLS, and all 3D strain parameters were independent predictors of CSF. Combination of sex, mitral E, and 3D GTS had the highest area under the curve (AUC) for identifying CSF (AUC, 0.81; P < 0.001). Integrated discrimination index (IDI) improved adding 3D GTS to the combined sex and mitral E model (IDI = 0.12, P = 0.01) or 2D GLS model (IDI = 0.14, P < 0.001). LV systolic function was impaired in CSF patients. 3D GTS had an independent and incremental value for predicting CSF compared with 2D echocardiography.

Reference values of the carotid elastic modulus using shear wave elastography and arterial stiffness change in coronary slow flow.

PURPOSE: Shear wave elastography (SWE) accurately and sensitively evaluates arterial wall stiffness by quantifying the elastic modulus (EM); however, the absence of reference values has precluded its widespread clinical application. This prospective cohort study aimed to establish reference values for the carotid EM using SWE; investigate the main determinants of the EM; and evaluate EM changes in coronary slow flow (CSF), which is characterized by delayed coronary opacification without evident obstructive lesion in epicardial coronary artery on angiography. METHOD: This study enrolled 169 healthy volunteers and 30 patients with CSF. The carotid maximum EM (EMmax), mean EM, and minimum EM were measured using SWE. CSF was diagnosed by thrombolysis in the myocardial infarction frame count during coronary angiography. RESULTS: No differences were found in the EM between the left and right carotid arteries and between men and women. Multiple linear regression analysis revealed that age was independently correlated with the EMmax, which progressively increased with age. Moreover, smoking had an independent influence on the EM after adjusting for age; smokers had higher EM than non-smokers. Age-specific reference values for the carotid EM were established. The EM was higher in patients with CSF than in controls after adjusting for age and smoking status. CONCLUSIONS: This study first established the reference values for the carotid EM using SWE. Age and smoking status were the main determinants of the EM. Patients with CSF had high EM. SWE can effectively and noninvasively evaluate arterial stiffness in patients with CSF.