The Risk of Venous Thromboembolism in Korean Patients with Breast Cancer: A Single-Center Experience.

The relationship between cancer and venous thromboembolism (VTE) has long been described. The risk of VTE in Asian patients with breast cancer remains largely unknown. This study described the incidence and risk factors of VTE in Korean patients with breast cancer. Data were collected from a retrospective database of patients who underwent breast cancer surgery between 2011 and 2020 at a single institution. The Cox proportional-hazards model was used to identify factors associated with VTE occurrences. Among the 2246 patients with breast cancer, 48 (2.1%) developed VTE during a median follow-up period of 53 months. The average incidence of VTE was 459 per 100,000 person-years. Age ≥ 60 years, male sex, chronic kidney disease, reconstructive procedures, and stage II or higher were independent predictive factors for VTE. VTE was associated with poor disease-free survival (hazard ratio (HR), 6.140; 95% confidence interval (CI), 3.480-10.835), and overall survival (HR, 8.842; 95% CI 4.386-17.824). Most VTE events were manageable with anticoagulation; three (6.3%) patients died of VTE, despite intensive care. The incidence of VTE was significantly elevated in Korean patients with breast cancer. Since VTE has a negative effect on oncologic outcomes of breast cancer, clinicians should manage its risk throughout their lifetime.

Edoxaban-based long-term antithrombotic therapy in patients with atrial fibrillation and stable coronary disease: Rationale and design of the randomized EPIC-CAD trial.

BACKGROUND: Anticoagulants are the standard therapy for patients with atrial fibrillation (AF) and antiplatelet therapy for those with coronary artery disease (CAD). However, compelling clinical evidence is still lacking regarding the long-term maintenance strategy with the combination of anticoagulant and antiplatelet drugs in patients with AF and stable CAD. DESIGN: The EPIC-CAD trial is an investigator-initiated, multicenter, open-label randomized trial comparing the safety and efficacy of 2 antithrombotic strategies in patients with high-risk AF (CHA2DS2-VASc score ≥ 2 points) and stable CAD (≥6 months after revascularization for stable angina or ≥12 months for acute coronary syndrome; or medical therapy alone). Patients (approximately N = 1,038) will be randomly assigned at a 1:1 ratio to (1) monotherapy with edoxaban (a non-vitamin K antagonist oral anticoagulant) or (2) combination therapy with edoxaban plus a single antiplatelet agent. The primary endpoint is the net composite outcome of death from any cause, stroke, systemic embolism, myocardial infarction, unplanned revascularization, and major or clinically relevant nonmajor bleeding at 1 year after randomization. RESULTS: As of December 2021, approximately 901 patients had been randomly enrolled over 2 years at 18 major cardiac centers across South Korea. The completed enrollment is expected at the mid-term of 2022, and the primary results will be available by 2023. CONCLUSIONS: EPIC-CAD is a large-scale, multicenter, pragmatic design trial, which will provide valuable clinical insight into edoxaban-based long-term antithrombotic therapy in patients with high-risk AF and stable CAD.

The effects of additional electrical stimulation combined with repetitive transcranial magnetic stimulation and motor imagery on upper extremity motor recovery in the subacute period after stroke: A preliminary study.

BACKGROUND: To evaluate the therapeutic effects of additional electrical stimulation (ES) combined with low frequency (LF)-repetitive transcranial magnetic stimulation (rTMS) and motor imagery (MI) training on upper extremity (UE) motor function following stroke. METHODS: The participants with subacute stroke in the experimental group (n = 8) received LF rTMS + MI + active ES interventions, and those in control group (n = 9) received LF rTMS + MI + sham ES interventions. Interventions were performed 5 days a week for 2 weeks, for a total of 10 sessions. All participants were given the same dosage of conventional rehabilitation during the study period. The primary outcome measure was the UE Fugl-Meyer Assessment (FMA). The secondary outcome measures were the shoulder abduction and finger extension scores, modified Barthel Index, Purdue Pegboard Test, and finger tapping test. All scores were measured before and just after the intervention. RESULTS: After the 2-week intervention period, the FMA and modified Barthel Index scores were improved in both groups compared to baseline assessment (P < .001 in the experimental group and P = .008 in the control group). Of note, the change in FMA scores was significantly higher in the experimental group compared with that of the control group (P = .04). CONCLUSION: These results suggest that the use of LF rTMS + MI combined with additional ES lead to greater improvement of UE motor function after stroke. As such, this intervention may be a promising adjuvant therapy in UE motor training.

Association between 10-Year Atherosclerotic Cardiovascular Disease Risk and Vascular Endothelial Function in Patients with Vasospastic Angina.

BACKGROUND: Endothelial dysfunction is a predictor of atherosclerotic cardiovascular disease (ASCVD) and plays an important role in vasospastic angina (VA). OBJECTIVES: This study evaluated whether flow-mediated dilation (FMD) is also a good marker of 10-year ASCVD risk (10Y-ASCVDR) in patients with VA. METHODS: Based on their clinical history and coronary artery diameter stenosis (DS), patients were retrospectively enrolled into VA (DS <50% and positive ergonovine provocation), minor coronary artery disease (mCAD, DS <30%), and significant coronary artery disease (sCAD, DS ≥50%) groups. Endothelial function was evaluated by FMD. RESULTS: Each group contained 50 patients. The 10Y-ASCVDR was significantly higher in the sCAD group than in the VA and mCAD groups (10.86 ± 7.30, 4.71 ± 4.04, and 4.77 ± 4.30, respectively, p < 0.001). The FMD was significantly higher in the mCAD group than in the VA and sCAD groups (6.37 ± 4.25, 3.10 ± 2.23, and 3.07 ± 1.89, respectively, p < 0.001). A significant correlation was found between the FMD and 10Y-ASCVD in the mCAD group (r = -0.622, p < 0.001) and the sCAD group (r = -0.557, p < 0.001) but not in the VA group (r = -0.193, p = 0.179). After adjusting for potential confounders such as BMI, C-reactive protein, maximal coronary stenosis, and brachial-ankle pulse wave velocity, multivariate analysis showed that FMD was independently associated with 10Y-ASCVDR in all patients. However, when looking only at the VA group, FMD did not correlate independently with 10Y-ASCVDR. CONCLUSIONS: Unlike mCAD and sCAD, we found no correlation between 10Y-ASCVDR and endothelial function in VA. Thus, our results support that FMD is not a good marker of atherosclerotic cardiovascular risk in VA.

The Effects of Atorvastatin on Global Cerebral Ischemia-Induced Neuronal Death.

(1) Background and Purpose: Global cerebral ischemia-induced severe hypoxic brain damage is one of the main causes of mortality and long-term neurologic disability even after receiving early blood reperfusion. This study aimed to test the hypothesis that atorvastatin potentially has neuroprotective effects in global cerebral ischemia (GCI). (2) Methods: We performed two sets of experiments, analyzing acute (1-week) and chronic (4-week) treatments. For the vehicle (Veh) and statin treatments, 1 mL of 0.9% saline and 5 mg/kg of atorvastatin (ATOR) were administered orally. For histological analysis, we used the following staining protocols: Fluoro-Jade B and NeuN, 4-hydroxynonenal, CD11b and GFAP, IgG, SMI71, and vWF. Finally, we evaluated the cognitive function with a battery of behavioral tests. (3) Results: The GCI-ATOR group showed significantly reduced neuronal death, oxidative stress, inflammation, and BBB disruption compared with the GCI-Veh group. Moreover, the GCI-ATOR group showed decreased endothelial damage and VV proliferation and had significantly improved cognitive function compared with the GCI-Veh group in both models. (4) Conclusions: ATOR has neuroprotective effects and helps recover the cognitive function after GCI in rats. Therefore, administration of atorvastatin may be a therapeutic option in managing GCI after CA.

Transient Receptor Potential Melastatin 2 (TRPM2) Inhibition by Antioxidant, N-Acetyl-l-Cysteine, Reduces Global Cerebral Ischemia-Induced Neuronal Death.

A variety of pathogenic mechanisms, such as cytoplasmic calcium/zinc influx, reactive oxygen species production, and ionic imbalance, have been suggested to play a role in cerebral ischemia induced neurodegeneration. During the ischemic state that occurs after stroke or heart attack, it is observed that vesicular zinc can be released into the synaptic cleft, and then translocated into the cytoplasm via various cation channels. Transient receptor potential melastatin 2 (TRPM2) is highly distributed in the central nervous system and has high sensitivity to oxidative damage. Several previous studies have shown that TRPM2 channel activation contributes to neuroinflammation and neurodegeneration cascades. Therefore, we examined whether anti-oxidant treatment, such as with N-acetyl-l-cysteine (NAC), provides neuroprotection via regulation of TRPM2, following global cerebral ischemia (GCI). Experimental animals were then immediately injected with NAC (150 mg/kg/day) for 3 and 7 days, before sacrifice. We demonstrated that NAC administration reduced activation of GCI-induced neuronal death cascades, such as lipid peroxidation, microglia and astroglia activation, free zinc accumulation, and TRPM2 over-activation. Therefore, modulation of the TRPM2 channel can be a potential therapeutic target to prevent ischemia-induced neuronal death.

Predictors of survival following veno-arterial extracorporeal membrane oxygenation in patients with acute myocardial infarction-related refractory cardiogenic shock: clinical and coronary angiographic factors.

BACKGROUND: This study aimed to identify the determinant factors of survival in patients with acute myocardial infarction (AMI) and refractory cardiogenic shock (RCS) who underwent veno-arterial extracorporeal membrane oxygenation (ECMO). METHODS: Sixty-nine consecutive patients with AMI-related RCS were enrolled in the study. They were treated with ECMO and primary percutaneous coronary intervention (PCI). The clinical scores and coronary angiography (CAG) factors related to 100-day survival were evaluated. RESULTS: Thirty patients (43.5%) survived for more than 100 days. The CAG showed that 19 (27.5%) patients had left main disease (LMD). There were 17 (24.6%), 27 (39.1%), and 25 (36.3%) patients with one-vessel, two-vessel, and three-vessel disease, respectively. There were significant differences between the survivors and non-survivors in the simplified acute physiology score II (SAPSII) (65.4±17.2 vs. 83.1±13.0, P<0.001), sepsis-related organ failure assessment score (SOFA) (10.4±2.7 vs. 12.3±2.5, P=0.004), survival after veno-arterial extracorporeal membrane oxygenation score (SAVE) (-4.4±4.3 vs. -8.4±3.1, P<0.001), CPR time (15.8±16.6 vs. 30.0±29.5, P=0.048), LMD [4 (13.3%) vs. 15 (38.5%), P=0.029], and number of coronary artery disease (NCAD) (P<0.001). Multivariate logistic regression analysis showed that NCAD (OR 3.788, P=0.008) was one of the independent predictors of mortality. The ROC analysis showed that SAPSII (AUC 0.786, P<0.001), SOFA (AUC 0.715, P=0.002), and SAVE (AUC 0.766, P<0.001) equally predict mortality. The combined NCAD parameters more accurately predicted mortality and differences in the AUC values (d-AUC) between SAPSII plus NCAD vs. SAPSII (d-AUC 0.073, z=2.256, P=0.024), SOFA plus NCAD vs. SOFA (d-AUC 0.058, z=2.773, P=0.006), and SAVE plus NCAD vs. SAVE (d-AUC 0.036, z=2.332, P=0.020). CONCLUSIONS: The SAPSII, SOFA, and SAVE scores predict the prognosis of ECMO-treated AMI patients with RCS. The CAG findings reinforce the predictive power of each score.

Brain natriuretic peptide levels predict 6-month mortality in patients with cardiogenic shock who were weaned off extracorporeal membrane oxygenation.

There are limited data regarding the association between brain natriuretic peptide (BNP) levels obtained after weaning from extracorporeal membrane oxygenation (ECMO) and the outcomes of patients with acute coronary syndrome (ACS)-associated cardiogenic shock.We prospectively obtained data regarding patients (aged ≥ 19 years) with ACS-associated cardiogenic shock who received ECMO and were subsequently weaned off the treatment. BNP levels were collected at 5 time points: pre-ECMO implantation, post-ECMO implantation, pre-ECMO weaning, day 1 after ECMO weaning, and day 5 after ECMO weaning.Of 48 patients with ACS-related cardiogenic shock, 33 were included in this analysis. Mean patient age was 59.0 (50.0-66.5) years, and 5 patients (15.2%) were women. Eight patients had asystole/pulseless electrical activity before ECMO and 14 (42.4%) had 3-vessel disease on coronary angiography. During the 6-month follow up, 12 (36.4%) patients died. BNP levels after ECMO weaning were significantly different between 6-month survivors and non-survivors. Cox proportional hazards model revealed that BNP levels (tertiles) on days 1 and 5 after ECMO weaning were significantly associated with 6-month mortality (hazard ratio, 7.872; 95% confidence interval, 1.870-32.756; 8.658 and 1.904-39.365, respectively). According to the Kaplan-Meier curves, the first tertile had significantly longer survival compared to the third tertile for both days 1 and 5 after ECMO weaning.Post-ECMO weaning BNP levels (days 1 and 5) were significantly associated with increased 6-month mortality in patients with ACS complicated by refractory cardiogenic shock who were weaned off ECMO.

The angiography-guided spot versus entire stenting in patients with long coronary lesions trial: Study design and rationale for a randomized controlled trial protocol.

BACKGROUND: /Purpose: Long-stenting, even with a second-generation drug-eluting stent (DES), is an independent predictor of restenosis and stent thrombosis in patients with long coronary lesions. Spot-stenting, i.e., selective stenting of only the most severe stenotic segments of a long lesion, may be an alternative to a DES. The purpose of this study is to compare the one-year clinical outcomes of patients with spot versus entire stenting in long coronary lesions using a second-generation DES. METHOD: This study is a randomized, prospective, multi-center trial comparing long-term clinical outcomes of angiography-guided spot versus entire stenting in patients with long coronary lesions (≥25 mm in length). The primary endpoint is target vessel failure (TVF) at 12 months, a composite of cardiac death, target vessel-related myocardial infarction, and target vessel revascularization (TVR). A total of 470 patients are enrolled for this study according to sample size calculations. This study will be conducted to evaluate the non-inferiority of spot stenting compared to entire stenting with zotarolimus-eluting stents (ZES). RESULTS: This study is designed to evaluate the clinical impact of spot-stenting with ZESs for TVF due to possible edge restenosis or non-target lesion revascularization. Theoretically, spot-stenting may decrease the risk of TVR and the extent of endothelial dysfunction. CONCLUSION: This SPOT trial will provide clinical insight into spot-stenting with a current second-generation DES as a new strategy for long coronary lesions.

Self-blood pressure monitoring is associated with improved awareness, adherence, and attainment of target blood pressure goals: Prospective observational study of 7751 patients.

We investigated whether self-blood pressure monitoring (SBPM) can improve the control rate of blood pressure (BP), adherence of antihypertensive medications, and the awareness of the importance of BP control in hypertensive patients. A total of 7751 patients who visited the outpatient clinics of private and university hospitals in Korea were given automatic electronic BP monitors and were recommended to measure their BP daily at home for 3 months. Changes in office BP, attainment of target BP, adherence to taking antihypertensive drugs, and awareness of BP were compared before and after SBPM. Patients and physicians were surveyed on their perception of BP and SBPM. Mean BP significantly decreased from 142/88 to 129/80 mm Hg (P < .001), and attainment of the target BP increased from 32% to 59% (P < .001) after SBPM. Drug non-adherence, which was defined as patient's not taking medication days per week, decreased significantly from 0.86 days to 0.53 days (P < .001). The rate of awareness of the BP goal increased from 57% to 81% (P < .001). Patients estimated that their mean BP was 125/81 mm Hg, but their actual mean BP was 142/88 mm Hg. Awareness about the importance of SBPM increased from 90% to 98%. The rate of SBPM ≥ once per week further increased, from 34% to 96%. In conclusion, SBPM is associated with reduced BP, better BP control rate, greater drug adherence, and improved perception of BP by the patients.

Association Between Intra-arterial Invasive Central and Peripheral Blood Pressure and Endothelial Function (Assessed by Flow-Mediated Dilatation) in Stable Coronary Artery Disease.

BACKGROUND: Endothelial function is an independent predictor of coronary artery disease (CAD) and is regulated by a number of factors, including blood pressure. OBJECTIVES: The current study was designed to test the hypothesis that intra-arterial invasive central blood pressure is strongly associated with endothelial function in patients with CAD. METHODS: In patient with CAD (diameter stenosis ≥30%), invasive central (aortic) and left peripheral (brachial) blood pressures were determined during transradial coronary angiography. The endothelial function was evaluated by way of flow-mediated dilatation (FMD) of the brachial artery. RESULTS: We enrolled 413 consecutive patients. There were 260 patients with significant CAD (sCAD, diameter stenosis ≥50%) and 153 patients with nonsignificant CAD (nsCAD, diameter stenosis <50% and ≤30%). FMD was significantly and inversely correlated with central and peripheral parameters in terms of systolic blood pressure, mean arterial pressure, and pulse pressure (PP) (r = -0.332, r = -0.184, and r = -0.407, respectively, all P < 0.001) and (r = -0.303, r = -0.190, and r = -0.319, respectively, all P < 0.001). Compared with sCAD, there was closer correlation between central PP with FMD in nsCAD (r = -0.548 vs. r = -0.345, both P < 0.001). After adjusting potential confounders such as age, body mass index and high-sensitivity C-reactive protein, multivariate analysis showed that FMD remained independently associated with central PP, degree of coronary artery stenosis, and brachial-ankle pulse wave velocity in all patients. In patients with nsCAD, the multivariate analysis showed that only central PP was independently correlated with FMD. CONCLUSIONS: In patients with stable CAD, a decline in endothelial function is most closely associated with invasive central pulse pressure.

The Effects of Sodium Dichloroacetate on Mitochondrial Dysfunction and Neuronal Death Following Hypoglycemia-Induced Injury.

Our previous studies demonstrated that some degree of neuronal death is caused by hypoglycemia, but a subsequent and more severe wave of neuronal cell death occurs due to glucose reperfusion, which results from the rapid restoration of low blood glucose levels. Mitochondrial dysfunction caused by hypoglycemia leads to increased levels of pyruvate dehydrogenase kinase (PDK) and suppresses the formation of ATP by inhibiting pyruvate dehydrogenase (PDH) activation, which can convert pyruvate into acetyl-coenzyme A (acetyl-CoA). Sodium dichloroacetate (DCA) is a PDK inhibitor and activates PDH, the gatekeeper of glucose oxidation. However, no studies about the effect of DCA on hypoglycemia have been published. In the present study, we hypothesized that DCA treatment could reduce neuronal death through improvement of glycolysis and prevention of reactive oxygen species production after hypoglycemia. To test this, we used an animal model of insulin-induced hypoglycemia and injected DCA (100 mg/kg, i.v., two days) following hypoglycemic insult. Histological evaluation was performed one week after hypoglycemia. DCA treatment reduced hypoglycemia-induced oxidative stress, microglial activation, blood-brain barrier disruption, and neuronal death compared to the vehicle-treated hypoglycemia group. Therefore, our findings suggest that DCA may have the therapeutic potential to reduce hippocampal neuronal death after hypoglycemia.

Carvacrol Attenuates Hippocampal Neuronal Death after Global Cerebral Ischemia via Inhibition of Transient Receptor Potential Melastatin 7.

Over the last two decades, evidence supporting the concept of zinc-induced neuronal death has been introduced, and several intervention strategies have been investigated. Vesicular zinc is released into the synaptic cleft, where it then translocates to the cytoplasm, which leads to the production of reactive oxygen species and neurodegeneration. Carvacrol inhibits transient receptor potential melastatin 7 (TRPM7), which regulates the homeostasis of extracellular metal ions, such as calcium and zinc. In the present study, we test whether carvacrol displays any neuroprotective effects after global cerebral ischemia (GCI), via a blockade of zinc influx. To test our hypothesis, we used eight-week-old male Sprague⁻Dawley rats, and a GCI model was induced by bilateral common carotid artery occlusion (CCAO), accompanied by blood withdrawal from the femoral artery. Ischemic duration was defined as a seven-minute electroencephalographic (EEG) isoelectric period. Carvacrol (50 mg/kg) was injected into the intraperitoneal space once per day for three days after the onset of GCI. The present study found that administration of carvacrol significantly decreased the number of degenerating neurons, microglial activation, oxidative damage, and zinc translocation after GCI, via downregulation of TRPM7 channels. These findings suggest that carvacrol, a TRPM7 inhibitor, may have therapeutic potential after GCI by reducing intracellular zinc translocation.

Effects of Protocatechuic Acid (PCA) on Global Cerebral Ischemia-Induced Hippocampal Neuronal Death.

Global cerebral ischemia (GCI) is one of the main causes of hippocampal neuronal death. Ischemic damage can be rescued by early blood reperfusion. However, under some circumstances reperfusion itself can trigger a cell death process that is initiated by the reintroduction of blood, followed by the production of superoxide, a blood⁻brain barrier (BBB) disruption and microglial activation. Protocatechuic acid (PCA) is a major metabolite of the antioxidant polyphenols, which have been discovered in green tea. PCA has been shown to have antioxidant effects on healthy cells and anti-proliferative effects on tumor cells. To test whether PCA can prevent ischemia-induced hippocampal neuronal death, rats were injected with PCA (30 mg/kg/day) per oral (p.o) for one week after global ischemia. To evaluate degenerating neurons, oxidative stress, microglial activation and BBB disruption, we performed Fluoro-Jade B (FJB), 4-hydroxynonenal (4HNE), CD11b, GFAP and IgG staining. In the present study, we found that PCA significantly decreased degenerating neuronal cell death, oxidative stress, microglial activation, astrocyte activation and BBB disruption compared with the vehicle-treated group after ischemia. In addition, an ischemia-induced reduction in glutathione (GSH) concentration in hippocampal neurons was recovered by PCA administration. Therefore, the administration of PCA may be further investigated as a promising tool for decreasing hippocampal neuronal death after global cerebral ischemia.

Clinical Meaning of the Ratio of Brachial Pre-Ejection Period to Brachial Ejection Time in Patients with Left Ventricular Systolic Dysfunction.

An increase in the ratio of the brachial pre-ejection period to brachial ejection time [pre-ejection period (PEP)/ET] is correlated with a decrease of left ventricular ejection fraction (LVEF). The current study was designed to test the hypothesis that the change value (Δ) of PEP/ET is a useful indicator of Δ LVEF in patients with left ventricular systolic dysfunction.We consecutively enrolled 104 patients with left ventricular systolic dysfunction (LVEF < 45%). PEP/ET, B-type natriuretic peptide (BNP), and LVEF were evaluated at baseline and at 6-month follow-up. Compared with the baseline measurements, the 6-month values of ΔLVEF, ΔBNP, and ΔPEP/ET were 9.8% ± 9.0% (from 36.3% ± 9.2% to 46.3% ± 12.5%, P < 0.001), -168.5 ± 255.4 (from 271.4 ± 282.5 to 104.1 ± 129.6, P < 0.001), and -0.060 ± 0.069 (from 0.413 ± 0.097 to 0.358 ± 0.079, P < 0.001), respectively. There were significant correlations between LVEF and PEP/ET and between LVEF and BNP in both the initial (r = -0.316, P = 0.001 and r = -0.598, P < 0.001, respectively) and 6-month follow-up (r = -0.307, P = 0.003 and r = -0.701, P < 0.001, respectively). The Steiger's Z test showed that BNP had a significantly stronger correlation with LVEF compared with the correlations between LVEF and PEP/ET in both the initial and 6-month studies (Z = 2.471, P = 0.013 and Z = 3.575, P < 0.001, respectively). There were also significant correlations between ΔLVEF and ΔPEP/ET (r = -0.515, P < 0.001) and between ΔLVEF and ΔBNP (r = -0.581, P < 0.001); however, there was no difference between the correlations for ΔLVEF and ΔPEP/ET versus ΔLVEF and ΔBNP (Steiger's Z = 0.600, P = 0.545).In patients with left ventricular systolic dysfunction not only ΔBNP but also ΔPEP/ET could be a simple indicator of predicting change of LVEF.

Ossabaw Pigs With a PCSK9 Gain-of-Function Mutation Develop Accelerated Coronary Atherosclerotic Lesions: A Novel Model for Preclinical Studies.

BACKGROUND: Ossabaw pigs are unique miniature swine with genetic predisposition to develop metabolic syndrome and coronary atherosclerosis after extended periods receiving atherogenic diets. We have hypothesized that transgenic Ossabaw swine expressing chimp PCSK9 (proprotein convertase subtilisin-like/kexin type 9) containing the D374Y gain of function would develop familial hypercholesterolemia and coronary artery plaques more rapidly than Landrace swine with the same transgene. METHODS AND RESULTS: Ossabaw and Landrace PCSK9 gain-of-function founders were generated by Sleeping Beauty transposition and cloning. Histopathologic findings in the Ossabaw founder animal showed more advanced plaques and higher stenosis than in the Landrace founder, underscoring the Ossabaw genetic predisposition to atherosclerosis. We chose to further characterize the Ossabaw PCSK9 gain-of-function animals receiving standard or atherogenic diets in a 6-month longitudinal study using computed tomography, magnetic resonance (MR) imaging, intravascular ultrasound, and optical coherence tomography, followed by pathological analysis of atherosclerosis focused on the coronary arteries. The Ossabaw model was consistently hypercholesterolemic, with or without dietary challenge, and by 6 months had consistent and diffuse fibrofatty or fibroatheromatous plaques with necrosis, overlying fibrous caps, and calcification in up to 10% of coronary plaques. CONCLUSIONS: The Ossabaw PCSK9 gain-of-function model provides consistent and robust disease development in a time frame that is practical for use in preclinical therapeutic evaluation to drive innovation. Although no animal model perfectly mimics the human condition, this genetic large-animal model is a novel tool for testing therapeutic interventions in the context of developing and advanced coronary artery disease.

Combined Treatment With Dichloroacetic Acid and Pyruvate Reduces Hippocampal Neuronal Death After Transient Cerebral Ischemia.

Transient cerebral ischemia (TCI) occurs when blood flow to the brain is ceased or dramatically reduced. TCI causes energy depletion and oxidative stress, which leads to neuronal death and cognitive impairment. Dichloroacetic acid (DCA) acts as an inhibitor of pyruvate dehydrogenase kinase (PDK). Additionally, DCA is known to increase mitochondrial pyruvate uptake and promotes glucose oxidation during glycolysis, thus enhancing pyruvate dehydrogenase (PDH) activity. In this study, we investigated whether the inhibition of PDK activity by DCA, which increases the rate of pyruvate conversion to adenosine triphosphate (ATP), prevents ischemia-induced neuronal death. We used a rat model of TCI, which was induced by common carotid artery occlusion and hypovolemia for 7 min while monitoring the electroencephalography for sustained isoelectric potential. Male Sprague-Dawley rats were given an intraperitoneal injection of DCA (100 mg/kg) with pyruvate (50 mg/kg) once per day for 2 days after insult. The vehicle, DCA only or pyruvate on rats was injected on the same schedule. Our study demonstrated that the combined administration of DCA with pyruvate significantly decreased neuronal death, oxidative stress, microglia activation when compared with DCA, or pyruvate injection alone. These findings suggest that the administration of DCA with pyruvate may enhance essential metabolic processes, which in turn promotes the regenerative capacity of the post-ischemic brain.

Peripheral vascular atherosclerosis in a novel PCSK9 gain-of-function mutant Ossabaw miniature pig model.

Hypercholesterolemia is a major risk factor for atherosclerosis. Remaining challenges in the management of atherosclerosis necessitate development of animal models that mimic human pathophysiology. We characterized a novel mutant pig model with DNA transposition of D374Y gain-of-function (GOF) cDNA of chimp proprotein convertase subtilisin/kexin type-9 (PCSK9), and tested the hypothesis that it would develop peripheral vascular remodeling and target organ injury in the kidney. Wild-type or PCSK9-GOF Ossabaw miniature pigs fed a standard or atherogenic diet (AD) (n = 7 each) were studied in vivo after 3 and 6 months of diet. Single-kidney hemodynamics and function were studied using multidetector computed tomography and kidney oxygenation by blood oxygen level-dependent magnetic resonance imaging. The renal artery was evaluated by intravascular ultrasound, aortic stiffness by multidetector computed tomography, and kidney stiffness by magnetic resonance elastography. Subsequent ex vivo studies included the renal artery endothelial function and morphology of abdominal aorta, renal, and femoral arteries by histology. Compared with wild type, PCSK9-GOF pigs had elevated cholesterol, triglyceride, and blood pressure levels at 3 and 6 months. Kidney stiffness increased in GOF groups, but aortic stiffness only in GOF-AD. Hypoxia, intrarenal fat deposition, oxidative stress, and fibrosis were observed in both GOF groups, whereas kidney function remained unchanged. Peripheral arteries in GOF groups showed medial thickening and development of atheromatous plaques. Renal endothelial function was impaired only in GOF-AD. Therefore, the PCSK9-GOF mutation induces rapid development of atherosclerosis in peripheral vessels of Ossabaw pigs, which is exacerbated by a high-cholesterol diet. This model may be useful for preclinical studies of atherosclerosis.

Prevalence of diastolic function and clinical impact on long-term outcome in takotsubo cardiomyopathy.

BACKGROUND: Takotsubo cardiomyopathy (TTC) is a syndrome characterized by transient regional systolic dysfunction of the left ventricle (LV). However, far fewer reports focused on the prevalence of left ventricular diastolic function (DF) and its impact on an adverse prognosis in TTC. METHODS: From January 2005 to October 2014, 205 consecutive TTC patients (mean age, 70±12years; 95% female) were studied. The patients underwent transthoracic echocardiography at the acute phase and recovery phase (mean, 38±16days after admission). RESULTS: DF was labeled as normal, mild, moderate and severe. At the acute phase, Abnormal DF was present in 108 patients (53%), and left ventricular ejection fraction (LVEF) <50% in 156 patients (76%). At the recovery phase, DF was unchanged for 104 patients (51%), 44 patients (21%) had worsened, 57 patients (28%) had improved in DF grade. 25 patients (12%) had an LVEF <50%. During 2years of follow-up, 34 patients developed clinical adverse events. Kaplan-Meier analysis estimated that the subgroup with unimproved DF and LVEF <50% at recovery phase had the worst 2-year survival. In multivariable analysis, unimproved DF with LVEF <50% and heart rate (HR) remained predictors of clinical adverse events. CONCLUSIONS: The current study demonstrated that consideration of both change of DF and LVEF allows identification of subgroups with divergent long-term prognoses in patients with TTC, and may indicate the need for a different management in the high-risk TTC patients.

Circulating osteogenic endothelial progenitor cell counts: new biomarker for the severity of coronary artery disease.

BACKGROUND: There is increasing evidence implying that the early and functionally highly active circulating endothelial progenitor cell (CEPC) phenotype (CD34-/CD133+/KDR+) with osteogenic potential (OCN+) might link between vascular atherosclerotic calcification and mechanisms of bone metabolism. We sought to evaluate the early OCN+ CEPC counts as an independent biomarker for the severity of coronary artery disease (CAD). METHODS: Peripheral blood samples were drawn from 593 patients undergoing clinically indicated coronary angiography. CAD severity was assessed by the presence of significant coronary artery stenosis (CAS) as well as an ordinal categorical variable. Subjects were followed for all-cause death over a median follow-up of 40months. RESULTS: OCN+ early CEPC counts (square-root transformed) were independently associated with the presence of significant CAS [odds ratio (OR) per standard deviation (SD) increment: 1.389, 95% confidence interval [CI]: 1.131 to 1.707, p=0.002). Similar association was observed with an increase in levels of CAS (OR: 1.353, 95% CI: 1.157 to 1.582, p<0.001). There was a weak tendency between OCN+ early CEPC counts and all-cause mortality (p=0.090), whereas the highest decile of OCN+ early CEPC counts had a 2.991-fold increased risk of all-cause death (p=0.047). CONCLUSIONS: We demonstrate for the first time an independent, significant, and strong correlation between OCN+ early CEPC counts and CAD severity. Additionally, very high numbers of OCN+ early CEPC tend to be linked to the risk of all-cause mortality.