Fibroblasts activation by embryonic signal switching: A novel mechanism of placental growth factor-induced cardiac remodeling.

INTRODUCTION: Cardiac remodeling is defined as cellular interstitial changes that lead dysfunction of the heart after injury. Placental growth factor (PlGF), a member of the VEGF family, has been reported to regulate cardiac hypertrophy in hemodynamic state. We therefore analyze the function of PlGF during cardiac remodeling using cardiac cells and fibroblasts, under Angiotensin II (AngII) stimulation. METHODS: PlGF overexpressed mouse embryonic fibroblasts derived from C57BL/6 mice, were made by deficient retrovirus vector, designated as C57/PlGF. Only retrovirus vector introduced C57 cells (C57/EV) were used as control. After AngII stimulation, wound scratching assay and MTT proliferation assay with or without p38 MAPK inhibitor, SB205580 were performed in retrovirally-introduced C57 cells. Reactive oxygen species (ROS) production, NF-kB activation, IL-6 and TNF-α production were also measured. Then we assessed AngII-induced cell proliferation of mouse cardiac fibroblasts (CFs) and rat primary cardiomyocytes incubating with C57/PlGF conditioned-medium. RESULTS: The PlGF production in C57/PlGF were confirmed by ELISA (1093.48 ± 3.5 pg/ml, ±SE). AngII-induced cell migration, proliferation and H2O2 production were increased in C57/PlGF compared with C57/EV. SB205580 inhibited the AngII-induced cell proliferation in C57/PlGF. In C57/PlGF cells, NF-kB activation was higher, followed by up-regulation of IL-6 and TNF-α production. CFs and cardiomyocytes proliferation increased when stimulated with C57/PlGF conditioned-medium. DISCUSSION: The activation of fibroblast is stimulated by PlGF signaling via p38 MAPK/NF-kB pathway accompanied by elevation of ROS and inflammatory response. Furthermore, these signals stimulate the activation of CFs and cardiomyocytes, indicating that high circulating level of PlGF have a potential to regulate cardiac remodeling.

Transarterial embolization to treat a massive hemothorax during mechanical circulatory support via puncturing of the extracorporeal membrane oxygenation circuit.

BACKGROUND: Current guidelines recommend the use of mechanical circulatory support (MCS) for patients with cardiogenic shock that is refractory to medical therapy. Bleeding is the most common complication of MCS. Transarterial embolization (TAE) is often performed to treat this complication, because it is a less invasive hemostatic procedure. However, the TAE option needs to be carefully considered during MCS, as the access route may be limited during MCS. CASE PRESENTATION: A man in his 70 s was diagnosed with acute myocardial infarction and underwent percutaneous coronary intervention via venoarterial extracorporeal membrane oxygenation (VA-ECMO) and Impella. During treatment in the intensive care unit, he suffered damage to a branch of the internal thoracic artery during a cardiac drainage procedure, which was subsequently treated via emergency TAE. An ECMO return cannula and an Impella sheath were inserted into the patient's right and left femoral arteries, respectively. An approach from the left brachial artery was selected, and the left internal thoracic artery was embolized. Subsequently, the patient required re-intervention to treat re-bleeding from another artery. Because it was difficult to target the target artery from the brachial one, owing to interference from the Impella catheter, the ECMO circuit near the return cannula was punctured and a guiding sheath was inserted. The ECMO flow and the patient's blood pressure decreased following placement of this guiding sheath. We were thus able to maintain the patient's blood pressure by increasing the infusion fluids and Impella flow, and embolize the target artery using a gelatin sponge to achieve hemostasis. CONCLUSION: When TAE is difficult to perform during MCS using an approach from the upper extremities, a lower extremity approach with a sheath inserted into the ECMO circuit may represent a viable alternative.

Clinical Implication and Optimal Management of Myocardial Bridging: Role of Cardiovascular Imaging.

Myocardial bridging (MB) was historically considered a benign structure as most people with MB are clinically asymptomatic. Recently, however, mounting evidence indicates that MB can cause adverse cardiac events owing to arterial systolic compression/diastolic restriction, atherosclerotic plaque progression upstream from MB, and/or vasospastic angina. In MB patients with refractory angina, the optimal treatment strategy should be determined individually based on versatile anatomic and hemodynamical assessments that often require multidisciplinary diagnostic approaches. The present review summarizes the clinical implication and management of MB, highlighting the role of imaging modalities currently available in this arena.

Impact of Serial Coronary Stenoses on Various Coronary Physiologic Indices.

BACKGROUND: Determining the functional significance of each individual coronary lesion in patients with serial coronary stenoses is challenging. It has been proposed that nonhyperemic pressure ratios, such as the instantaneous wave free ratio (iFR) and the ratio of resting distal to proximal coronary pressure (Pd/Pa) are more accurate than fractional flow reserve (FFR) because autoregulation should maintain stable resting coronary flow and avoid hemodynamic interdependence (cross-talk) that occurs during hyperemia. This study aimed to measure the degree of hemodynamic interdependence of iFR, resting Pd/Pa, and FFR in a porcine model of serial coronary stenosis. METHODS: In 6 anesthetized female swine, 381 serial coronary stenoses were created in the left anterior descending artery using 2 balloon catheters. The degree of hemodynamic interdependence was calculated by measuring the absolute changes in iFR, resting Pd/Pa, and FFR across the fixed stenosis as the severity of the other stenosis varied. RESULTS: The hemodynamic interdependence of iFR, resting Pd/Pa, and FFR was 0.039±0.048, 0.021±0.026, and 0.034±0.034, respectively (all P<0.001). When the functional significance of serial stenoses was less severe (0.70-0.90 for each index), the hemodynamic interdependence was 0.009±0.020, 0.007±0.013, and 0.017±0.022 for iFR, resting Pd/Pa, and FFR, respectively (all P<0.001). However, in more severe serial coronary stenoses (<0.60 for each index), hemodynamic interdependence was 0.060±0.050, 0.037±0.030, and 0.051±0.037 for iFR, resting Pd/Pa, and FFR, respectively (all P<0.001). CONCLUSIONS: When assessing serial coronary stenoses, nonhyperemic pressure ratios are affected by hemodynamic interdependence. When the functional significance of serial coronary stenoses is severe, the effect is similar to that which is seen with FFR.

Very late stent thrombosis lacking findings of the typical causes on optical coherence tomography in a patient with SARS-CoV-2.

A 50-year-old male was admitted to our hospital with sudden-onset chest pain. He was a current smoker with severe obesity and diabetes. He had a history of drug-eluting stent (DES) implantation in the left anterior descending artery (LAD) and had continuously taken clopidogrel. Eight days prior to admission, polymerase chain reaction testing confirmed that he was positive for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Emergent coronary angiography revealed total occlusion of previously implanted DES in LAD. Optical coherence tomography (OCT) images demonstrated the presence of large white thrombus within the well-expanded DES with homogenous neointima. There were no findings of malapposed strut, uncovered strut, intimal disruption, or neoatherosclerosis through the stented segment. Subsequent dilation using a drug-coated balloon successfully restored coronary flow in LAD. We experienced a case of very late stent thrombosis without findings of the typical causes on OCT images nor discontinuation of antiplatelet therapy in a patient with SARS-CoV-2. The present case suggests that SARS-CoV-2 infection may induce stent thrombosis irrespective of the presence of known causes and the status of antiplatelet therapy. Learning objectives: The underlying causes of very late stent thrombosis (VLST) include strut malapposition, neoatherosclerosis, uncovered struts and stent underexpansion in addition to inadequate discontinuation of antiplatelet therapy and/or systemic hyper coagulable state. The present case of VLST lacking those factors suggests the enhanced hyper thrombogenicity irrespective of the presence of known causes and the status of antiplatelet therapy in patients with severe acute respiratory syndrome coronavirus type 2.

Impact of Diastolic Vessel Restriction on Quality of Life in Symptomatic Myocardial Bridging Patients Treated With Surgical Unroofing: Preoperative Assessments With Intravascular Ultrasound and Coronary Computed Tomography Angiography.

[Figure: see text].

Successful Retrieval of Entrapped Guide Extension Catheter in the Right Coronary Artery with Heavy Calcifications.

Usage of an optimal guide extension catheter often helps successful outcomes in complex percutaneous coronary intervention. Here, we report a case of successfully retrieving a guide extension catheter entrapped by a coronary stent in the middle RCA. The guide extension catheter was retrieved by anchoring with the stent delivery balloon. Also, our in vitro experiment demonstrated that a "deep seating method" and an "anchoring guide extension catheter method" could be effective in bailing out guide extension catheter entrapment.

Empagliflozin attenuates neointimal hyperplasia after drug-eluting-stent implantation in patients with type 2 diabetes.

The effects of empagliflozin, a sodium-glucose co-transporter 2 inhibitor, on neointimal response after drug-eluting-stent (DES) implantation remains unknown. Insufficiently controlled diabetes patients with coronary artery disease planned for DES stenting were consecutively enrolled. The patients were assigned to receive empagliflozin in addition to standard therapy or intensive therapy using other glucose-lowering drugs (oGLD). The primary endpoint was thickness of neointimal hyperplasia (NIH) 12 months after stenting assessed by optical coherence tomography (OCT). A total of 28 patients were analyzed (n = 15 in the empagliflozin group, n = 13 in the oGLD group). The levels of glucose profile were not significantly different between both groups at follow-up [HbA1c; 7.2 ± 0.8 vs 7.3 ± 0.9%, p = 0.46]. In OCT analysis, neointima was significantly less in the empagliflozin group than the oGLD group [mean NIH thickness: 137 ± 32 vs 168 ± 39 µm, p = 0.02]. Changes of systolic and diastolic blood pressure (BP), changes of body mass index, and changes of hematocrit after additional treatment were significantly associated with NIH attenuation, whereas no correlation was observed in changes in blood glucose parameters. Multivariate logistic regression analysis revealed that changes in systolic BP was the strongest predictor for NIH attenuation, followed by changes in diastolic BP. In patients with type 2 diabetes, standard plus empagliflozin attenuated neointimal progression as compared with intensive standard therapy after DES implantation. Our data possibly support a beneficial effect of empagliflozin in type 2 diabetes required for coronary revascularization therapy.

Repetitive restenosis in a biodegradable polymer sirolimus-eluting stent with hypersensitivity reaction: a case report.

BACKGROUND: Hypersensitivity reaction is a classic cause of in-stent restenosis (ISR) in coronary stents, typically reported in bare-metal stents and first-generation drug-eluting stents. Biodegradable polymer sirolimus-eluting stent (BP-SES) was developed with the concept of biocompatibility, and there has been no report of ISR of BP-SES with hypersensitivity reaction. CASE SUMMARY: An 81-year-old woman presented with ST-elevation acute inferior myocardial infarction. Primary percutaneous coronary intervention was performed for the culprit lesion in the left circumflex artery with a permanent polymer everolimus-eluting stent (PP-EES), followed by BP-SES implantation in the left anterior descending artery. Eight months later, coronary angiography showed total occlusion of the PP-EES and diffuse ISR in the BP-SES, treated with a paclitaxel-eluting balloon. Fluorodeoxyglucose with positron emission tomography showed increased uptake around the BP-SES, and cardiac magnetic resonance imaging revealed a late gadolinium-enhanced area around both stents. Four months later, she developed re-ISR in the BP-SES, and optical coherence tomography demonstrated diffuse-layered neointimal hyperplasia with microvascularization and peri-strut low-intensity area. She was successfully treated with coronary artery bypass grafting. DISCUSSION: Our case demonstrated repetitive short-term ISR of the BP-SES. Observation by both intravascular and non-invasive imaging modalities suggested the presence of hypersensitivity reaction localized in the stent. Hypersensitivity to the metal may be a possible mechanism because both stents are composed of L605 cobalt-chromium alloy. This is the first report of ISR of a BP-SES with hypersensitivity reaction. Non-invasive imaging can be useful to assess this critical condition.

Linagliptin Suppresses Electrical and Structural Remodeling in the Isoproterenol Induced Myocardial Injury Model.

The effect of DPP-4 inhibitor on the electrical and structural remodeling in myocardial injury has not been evaluated. We hypothesized that linagliptin, DPP-4 inhibitor, suppresses myocardial remodeling in the isoproterenol (ISP)-induced myocardial injury model.Sprague-Dawley rats were assigned to 3 groups: 1) sham group, 2) ISP group (subcutaneous ISP injection of 70 mg/kg), and 3) ISP + linagliptin (ISP + Lin) (5 mg/kg/day, p.o.) group. Serum was sampled on day 1 (acute phase) and day 7 (sub-acute phase) to evaluate derivatives of reactive oxidative metabolites (d-ROMs). The electrophysiological study was performed in sub-acute phase for the evaluation of the ventricular effective refractory period (VERP) and monophasic action potential duration (MAPD). The VERP and MAPD were markedly prolonged in the ISP group in comparison with the sham (MAPD20: 14 ± 6 versus 11 ± 3 ms, MAPD90: 57 ± 8 versus 44 ± 7 ms, VERP: 74 ± 22 versus 38 ± 10 ms, P < 0.05). In contrast in the ISP + Lin group, such prolongations were suppressed, and the parameters were shorter than the ISP group (MAPD20: 9 ± 2 ms, MAPD90: 35 ± 6 ms, VERP: 52 ± 13 ms, P < 0.05). ISP treatment induced myocardial injury. The injured area was reduced in the ISP + Lin group in comparison with the ISP group (P < 0.05). Serum d-ROMs level in acute phase was higher in ISP group than the other 2 groups (sham: 214 ± 55 versus ISP: 404 ± 45 versus ISP + Lin: 337 ± 20 U.CARR, P < 0.05).Linagliptin suppressed structural and electrical changes, possibly through the antioxidative effect, in this myocardial injury model.

Stent Recoil in Overlapping Stent 18 Years After Wiktor Stent Implantation.

In this paper, we look at the case of a 79 years old male who received a Wiktor stent (WS) implantation for myocardial infarction in proximal left anterior descending artery 18 years ago. Eleven years later, an Everolimus eluting stent (EES; Xience V™) was implanted for the proximal edge restenosis of WS from mid left main trunk to the middle part of WS. Seven years after EES implantation, the angiography and optical coherence tomography revealed in-stent restenosis with severe stent recoil just distal to the overlapping zone of WS. In the present case, stent recoil seems to have occurred due to different radial stiffness and flexibility between the two stents.

Impact of underlying plaque type on strut coverage in the early phase after drug-eluting stent implantation.

BACKGROUND: The aim of this study was to investigate whether the underlying plaque type affects the neointimal coverage after drug-eluting stent implantation. METHODS: A total of 1793 struts in 22 zotarolimus-eluting stents were assessed using optical coherence tomography imaging within 3 months of implantation. Neointimal coverage was evaluated within 5 mm from each stent edge on cross-sectional optical coherence tomography images at every 1-mm interval. The percentage of struts covered by neointima was compared among the normal segment group, the fibrous plaque group, and the lipid plaque group on the basis of the underlying plaque type. RESULTS: The percentage of covered strut was significantly lower in the normal segment group than in the fibrous plaque group (35.9±30.2 vs. 57.1±31.0%, P<0.05) and the lipid plaque group (vs. 64.7±23.5%, P<0.01). The neointima was significantly thinner in the normal segment group than in the lipid plaque group (19.0±22.3 vs. 32.0±18.8 µm, P<0.01). The percentage of struts on the normal segment was significantly higher in cross-sections with a ratio of uncovered to total struts per section more than 0.3 than in cross-sections with a ratio up to 0.3 (32.4±31.7 vs. 19.5±33.8%, P<0.01). CONCLUSION: Struts on the normal segment were less covered and had thinner neointima than struts on the lipid plaque at the stent edge within 3 months after zotarolimus-eluting stent implantation. Caution should be exercised when implanting longer drug-eluting stents to achieve uniform strut coverage in the early phase.

Eosinophilic Myocarditis With Hypersegmented Granulocytes and Neutrophilia Without Eosinophilia: A Case Mimicking Neutrophilic Myocarditis.

We report a case of a 78-year-old woman with neutrophilia without eosinophilia who was pathologically diagnosed with eosinophilic myocarditis by myocardial biopsy. The biopsy specimen showed infiltrating granulocytes with hypersegmentation, mimicking neutrophils; however, they were confirmed to be eosinophils by Giemsa staining.

Lower Level of Low Density Lipoprotein Cholesterol is Associated with a Higher Increase in the Fractional Flow Reserve in Patients with Fixed-dose Rosuvastatin.

AIM: Fractional flow reserve (FFR) reflects on the diffuse atherosclerosis per coronary artery. It is unknown whether the statin therapy affects long term FFR after stenting. The aim of this study was to evaluate the long term FFR after stent implantation in patients who are intaking fixed-dose rosuvastatin. METHODS: A total of 22 patients with stable angina pectoris were enrolled. The values of FFR were measured before, immediately after, and 18 months after (follow-up day) the implantation of everolimus eluting stent (EES; Promus ElementTM or Promus Element PlusTM). A fixed dose of rosuvastatin at 5 mg/day was administrated to all patients. RESULTS: Of the 22 patients, 2 were excluded because of adverse effect of rosuvastatin and in-stent total occlusion after EES implantation. Overall, the values of FFR immediately after and 18 months after EES implantation did not show significant change (from 0.90±0.05 to 0.88±0.06, p=0.16). However, there was a significant negative correlation between low density lipoprotein (LDL) cholesterol level at follow-up day and changes in the value of FFR (p=0.01, r =－0.74). There was an increase in the FFR value after stenting in 8 out of 9 patients with LDL cholesterol level below 75 mg/dl (area under the curve 0.92, p=0.0005). CONCLUSIONS: LDL cholesterol level was associated with the change in the FFR value in patients following stent implantation. Lower LDL cholesterol tended to improve in the long-term FFR, underscoring the importance of lowering LDL cholesterol to prevent the progression of coronary atherosclerosis.

Effects on bone metabolism markers and arterial stiffness by switching to rivaroxaban from warfarin in patients with atrial fibrillation.

In recent years, direct oral anticoagulants (DOACs) of dabigatran, rivaroxaban, apixaban, edoxaban, which are all alternatives to warfarin, have been released. The use of DOACs is becoming more widespread in the clinical management of thrombotic stroke risk in patients with atrial fibrillation (AF). In large-scale clinical trials of each drug, DOACs were reported to inhibit intracranial hemorrhage, stroke, and death compared to warfarin. Warfarin is an endogenous vitamin K antagonist; therefore, patients who are taking warfarin must be prohibited from taking vitamin K. Vitamin K is an essential cofactor required for the ɤ-carboxylation of vitamin K-dependent proteins including coagulation factors, osteocalcin (OC), matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6). OC is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification in the vessel wall. GAS6 prevents the apoptosis of vascular smooth muscle cells. Therefore, decrease of blood vitamin K levels may cause osteoporosis, vascular calcification, and the inhibition of vessels angiogenesis. This study aimed to evaluate the effects of changing from warfarin to rivaroxaban on bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction. We studied 21 consecutive patients with persistent or chronic AF, who were treated with warfarin at least for 12 months. Warfarin administration was changed to rivaroxaban (10 or 15 mg/day) in all patients. Osteopontin (OPN), bone alkaline phosphatase (BAP), and under-carboxylated osteocalcin (ucOC) were measured. Pulse wave velocity (PWV) and augmentation index (AI) were also measured as atherosclerosis assessments. All measurements were done before and six months after the rivaroxaban treatment. There was a significant increase in serum level of BAP compared to baseline (12.5 ± 4.6 to 13.4 ± 4.1 U/L, P < 0.01). In contrast, there was a significant decrease in the serum level of ucOC (9.5 ± 5.0 to 2.7 ± 1.3 ng/ml, P < 0.01). Also, in the ucOC levels, there was a significant negative correlation between baseline values and baseline to 6-months changes in high ucOC group (r = -0.97, P < 0.01). The atherosclerosis- and osteoporosis-related biomarker, serum level of OPN were significantly decreased compared to baseline (268.3 ± 46.8 to 253.4 ± 47.1 ng/ml, P < 0.01). AI and PWV were significantly decreased after 6 months of treatment with rivaroxaban (33.9 ± 18.4 to 24.7 ± 18.4%, P = 0.04; 1638.8 ± 223.0 to 1613.0 ± 250.1 m/s, P = 0.03, respectively). Switching to rivaroxaban from warfarin in patients with atrial fibrillation was associated with an increase of bone formation markers and a decrease of bone resorption markers, and also improvements of PWV and AI.

Ezetimibe enhances and stabilizes anticoagulant effect of warfarin.

Ezetimibe reduces plasma levels of low-density lipoprotein cholesterol by inhibiting Niemann-Pick C1-like protein 1 (NPC1L1). A recent study demonstrated that NPC1L1 plays an important role in absorption of fat-soluble vitamins including vitamin K. We evaluated whether the add-on treatment of ezetimibe affects anticoagulation in patients taking warfarin. Between October 2007 and March 2015, the administration of ezetimibe was started to a total of 101 outpatients who were already on oral anticoagulation with warfarin. We retrospectively analyzed blood lipid levels, prothrombin time international normalized ratio (PT-INR) and time in therapeutic INR range (TTR). Seventy-one patients (70 %) showed increase in PT-INR after ezetimibe treatment (1.96 ± 0.45 to 2.20 ± 0.61, p < 0.001). It was necessary to reduce the warfarin dose in 9 of 101 patients for clinical indication. There was a significant positive correlation between change in PT-INR and statin usage at baseline (p = 0.03). The mean value of changes in PT-INR of patients with taking statin was significantly larger than that of patients without taking statin (0.34 ± 0.54 vs. 0.06 ± 0.36, p = 0.03). There was an increase in the TTR (52 ± 26 to 61 ± 23 %, p < 0.0001) and a decrease in the frequency to change the dose of warfarin after the ezetimibe treatment [45 times of 735 examination days (6 %) to 20 times of 695 examination days (3 %), p = 0.02]. Our data suggest possible drug interaction between warfarin and ezetimibe. Ezetimibe may increase and stabilize the anticoagulant effect of warfarin, especially in patients taking statins.

Teneligliptin improves left ventricular diastolic function and endothelial function in patients with diabetes.

Incretin hormones have been reported to have cytoprotective actions in addition to their glucose-lowering effects. We evaluated whether teneligliptin, a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, affects left ventricular (LV) function in patients with type 2 diabetes mellitus (T2DM). Twenty-nine T2DM patients not receiving any incretin-based drugs were enrolled and prescribed with teneligliptin for 3 months. Compared to baseline levels, hemoglobin A1c levels decreased (7.6 ± 1.0 % to 6.9 ± 0.7 %, p < 0.01) and 1,5-anhydro-D-glucitol levels increased (9.6 ± 7.2 µg/mL to 13.5 ± 8.7 µg/mL, p < 0.01) after treatment. Clinical parameters, including body mass index and blood pressure, did not show any difference before and after treatment. Three months after treatment, there were improvements in LV systolic and diastolic function [LV ejection fraction, 62.0 ± 6.5 % to 64.5 ± 5.0 %, p = 0.01; peak early diastolic velocity/basal septal diastolic velocity (E/e') ratio, 13.3 ± 4.1 to 11.9 ± 3.3, p = 0.01]. Moreover, there was an improvement in endothelial function (reactive hyperemia peripheral arterial tonometry [RH-PAT] index; 1.58 ± 0.47 to 2.01 ± 0.72, p < 0.01). There was a significant negative correlation between changes in the E/e' ratio and RH-PAT values. Furthermore, circulating adiponectin levels increased (27.0 ± 38.5 pg/mL to 42.7 ± 33.2 pg/mL, p < 0.01) without changes in patient body weight. Teneligliptin treatment was associated with improvements in LV function and endothelial functions, and an increase in serum adiponectin levels. These results support the cardio-protective effects of teneligliptin in T2DM patients and increase in serum adiponectin levels.