3D-Printing-Based Fluoroscopic Coronary Angiography Simulator Improves Learning Capability Among Cardiology Trainees.

Aim: One of the essential competencies of cardiology trainees is the ability to perform coronary angiography with good projection. Purpose: This study is a research and development study aimed at testing the effectiveness of 3D-printing-based fluoroscopic coronary angiography simulator as a learning medium for diagnostic coronary angiogram. Methods: Thirty-four cardiology trainees randomly were divided into two groups. Both groups took a pretest before the intervention. The first group (group A) studied using conventional learning media and underwent the first post-test. Afterward, they switched to a 3D-printing-based fluoroscopic coronary angiography simulator and underwent a second post-test. The second group (group B) studied using a 3D-printing-based fluoroscopic coronary angiography simulator, underwent the first post-test, switched to the conventional learning media, and underwent a second post-test. Results: The delta between the post-test I and the pretest of group B was 8.53, higher than the delta between the post-test I and the pretest of group A (5.21) with a significant difference (p = 0.003). In group A, the delta between post-test II and pretest was 9.65, higher than the delta between post-test I and pretest (5.21) with a significant difference (p < 0.001). Conclusion: 3D-printing-based fluoroscopic coronary angiography simulator is effective as a learning medium for coronary angiogram diagnostics.

CT-Derived 3D Printing for Coronary Artery Cannulation Simulator Design Manufacturing.

Mastering coronary angiography requires practice. Cadavers and animals do not accurately represent the human anatomical body, and practicing with actual patients has medical safety issues. Simulation offers safe and realistic conditions for cardiology intervention training. In this study, we propose a novel 3D printed simulator that contains physically realistic anatomy and has four access points. It increases safety for patients and students, and production is low-cost. We aimed to make and validate this simulator design as a prototype for coronary cannulation training. It was designed using computed tomography (CT) scan data of aorta, coronary, and heart models, and was printed by 3D printing with resin materials consisting of 75% or 85% clear resin and 25% or 15% flexible resin additive. The simulator was constructed with a camera above the simulator with a degree of LAO of 30°/0°, a display table, and an acrylic box. Twelve validators were interviewed for their expert opinions and analyzed by a qualitative method. They scored the simulator's suitability on a four-point Likert scale questionnaire. They described the simulator as having admirable values for all aspects (85.8%), curriculum suitability (92%), educational importance (94%), accuracy (83%), efficiency (78%), safety (87.5%), endurance (81.2%), aesthetics (80.7%), storage (85.4%), and affordability (85.8%).

The effect of oral sildenafil therapy on health-related quality of life in adults with pulmonary arterial hypertension related to uncorrected secundum atrial septal defect: a quasi experimental study.

BACKGROUND: Assessment of health-related quality of life (HRQoL) are often measured as an important patient-reported outcome (PRO) in clinical studies. Pulmonary arterial hypertension (PAH) is a common complication of atrial septal defect (ASD). This study aimed to compare the HRQoL of PAH related uncorrected secundum ASD at pre and post therapy with oral sildenafil therapy. METHODS: We conducted quasi experimental study at Sardjito General Hospital Yogyakarta since April 2016 to August 2017. Adults with PAH related uncorrected secundum ASD, listed on Congenital Heart Disease and Pulmonary Hypertension (COHARD-PH) registry, and met the inclusion and exclusion criteria were recruited as subject. Interview was done at pre and 12 weeks post oral sildenafil therapy 3 × 20 mg using the EQ-5D-3L questionnaire. Statistical analysis was done using Wilcoxon test and paired T-test to determine the differences of EQ-5D utility and EQ-VAS score at pre and post therapy. RESULTS: A total of 18 adult patients with PAH related to uncorrected secundum ASD were enrolled in this study (83.33% female; mean age 38.72 ± 10.81 years old). The most frequent reported problems pre therapy were pain/discomfort (83%) and anxiety/depression (78%). Wilcoxon test showed the median of EQ-5D utility score were increased after sildenafil therapy (before = 0.604, after = 0.664; Z = - 2703; p:0.007), respectively. Meanwhile, the paired T-test results showed an increase of EQ-VAS mean difference 6.67 ± 8.75 (p:0.005; 95% CI 2.32-11.02) after sildenafil therapy. CONCLUSION: The administration of oral sildenafil therapy 3 × 20 mg during 12 weeks in adult patients with PAH related uncorrected secundum ASD gives better HRQoL.

Platelet microparticle number is associated with the extent of myocardial damage in acute myocardial infarction.

INTRODUCTION: Activated platelets generate microparticles. Increased platelet microparticles occur in acute myocardial infarction (AMI) and contribute to intracoronary thrombosis and subsequent myocardial injury. This study aimed to investigate the impact of platelet microparticles on intracoronary thrombosis by assessing the relationship between platelet microparticles and the extent of myocardial damage in AMI. MATERIAL AND METHODS: This was a cross sectional study. The subjects were patients with acute coronary syndrome (ACS). Forty-one consecutive subjects with ACS admitted to intensive cardiovascular care unit were enrolled. The clinical spectrum of ACS comprised AMI (n = 26), both ST-elevation AMI (STEMI) and non-ST-elevation AMI (NSTEMI), and unstable angina (n = 15). Platelet microparticles were isolated from peripheral venous blood and detected with anti-CD42b-PE by the flow cytometry method. The extent of myocardial damage was determined by measuring the peak level of serial cardiac enzymes within 24 h of admission. RESULTS: Subjects with AMI had a significantly higher number of platelet microparticles than those with unstable angina (4855 ±4509/µl vs. 2181 ±1923/µl respectively; p = 0.036). Subjects with STEMI had the highest number of platelet microparticles, but no significant difference was detected as compared to those with NSTEMI (5775 ±5680/µl vs. 3601 ±1632/µl). The number of platelet microparticles in AMI was positively associated with the extent of myocardial damage (peak CK-MB: r = 0.408, p = 0.019 and peak GOT: r = 0.384, p = 0.026). CONCLUSIONS: The number of platelet microparticles was increased in AMI as compared to unstable angina and associated with the extent of myocardial damage.

Anomalous Origination of Right Coronary Artery from Left Sinus in Asymptomatic Young Male Presenting with Positive Ischemic Response on Treadmill Test.

Anomalous origination of coronary artery from the opposite sinus (ACAOS) is a rare coronary artery anomaly. Right ACAOS with interarterial course is a type of ACAOS, which conveys a high risk for myocardial ischemia or sudden death. We reported a case of right ACAOS with interarterial course in otherwise healthy young male. He was asymptomatic, until an obligatory medical check-up with treadmill test showed a sign of positive ischemic response. Further work-up revealed that he had right ACAOS with interarterial course. Watchful observation was applied to him, while strenuous physical activity and competitive sport were absolutely prohibited.

Predictive value of different estimated glomerular filtration rates on hospital adverse events following acute myocardial infarction.

AIM: to assess whether different glomerular filtration rate (GFR) equations render different predictive value on hospital adverse events in patients hospitalised due to acute myocardial infarction. METHODS: the study design is cross-sectional. Data from consecutive patients with acute myocardial infarction were analyzed. Three different estimated GFR equations, i.e. Cockroft-Gault (eGFRC-G), MDRD (eGFRMDRD) and CKD-EPI (eGFRCKD-EPI) were calculated. Hospital adverse events in these study patients were recorded. The predictive values of these eGFRs on hospital adverse events were compared with ROC curve. Univariate and multivariable analysis to assess which GFR equation as independent predictor for hospital adverse events were performed. RESULTS: among 103 study patients, 49 patients (47.6%) experienced hospital adverse events. Proportion of hospital adverse events were significantly associated with eGFRMDRD (p<0.01) and eGFRCKD-EPI (p=0.02), but not with eGFRC-G (p=0.10). Hospital adverse events were better predicted by eGFRMDRD than by eGFRCKD-EPI (AUC, 0.698; 95%CI: 0.596-0.800, p<0.01 versus AUC, 0.693; 95%CI: 0.591-0.796, p<0.01). Multivariable analysis showed moderate (adjusted OR 3.50; 95%CI: 1.38-8.85, p<0.01) and severe (adjusted OR 8.13, 95%CI: 1.38-47.91, p=0.02) kidney dysfunctions based on eGFRMDRD were independent predictors for hospital adverse events. CONCLUSION: an eGFR based on MDRD gave better predictive value than eGFR based on CKD-EPI on hospital adverse events among acute myocardial infarction. Moderate and severe kidney dysfunctions based on eGFRMDRD were independent predictors for hospital adverse events following acute myocardial infarction.

Association between levels of circulating soluble CD40 ligand on admission and in-hospital events among acute coronary syndrome patients.

AIM: to investigate the association between on admission circulating sCD40L level and in-hospital events among patients admitted with acute coronary syndrome. METHODS: a short prognostic study which recruited consecutively patients with acute coronary syndrome (ACS) admitted in Intensive Coronary Care Unit (ICCU). INCLUSION CRITERIA: between 35-70 years old, onset of chest pain 24 hours and approved informed consent. Patients with acute infection, renal failure, heart failure, liver cirrhosis, chronic inflammation, venous thromboemboli, malignancies and pregnancy were excluded. Blood samples of sCD40L was withdrawn on admission and measured with ELISA. Follow-up was conducted during intensive hospitalization. In-hospital events were re-infarction, acute heart failure, cardiogenic shock and mortality. RESULTS: of 77 study patients, 64 (83%) were male with mean age 55 years old. In-hospital events occurred in 33 (43%) patients, namely mortality 6 (18%), acute heart failure 25 (75%) and cardiogenic shock 2 (6%). The level of circulating sCD40L was significantly higher in patients with in-hospital events compared with those without in-hospital events (8559.6 pg/ml vs. 7393.8 pg/ml respectively, p value <0.05). Using ROC curve, we determined cut-off point 7107.0 pg/ml. On multivariate analysis, high sCD40L (7107.0 pg/ml) had a trend to increase the risk of in-hospital events, although statistically not significant (adjusted OR 1.66, 95% CI : 0.56-4.87; p value 0.36). CONCLUSION: on admission circulating sCD40L level was higher in patients with in-hospital events. Nonetheless, high sCD40L level did not significantly associate with increasing risk to develop in-hospital events among ACS.

On Arrival High Blood Glucose Level is Associated With Detrimental and Fatal Hospitalization Outcomes for Acute Coronary Syndrome.

BACKGROUND: High blood glucose level is frequently encountered in acute coronary syndrome. We investigated the effects of high blood glucose measured on arrival on hospitalization adverse events in acute coronary syndrome. Our study patients were Javanese in ethnicity, which constitute half of population in Indonesia. We hypothesized that elevated blood glucose has detrimental effects on hospitalization for acute coronary syndrome. METHODS: We designed an observasional cohort study and recruited 148 consecutive patients with acute coronary syndrome. Venous blood was collected on hospital arrival. High blood glucose level was determined as plasma glucose > 140 mg/dL. Adverse hospitalization events were recorded, i.e. mortality, acute heart failure, cardiogenic shock and heart rhythm disorders. Echocardiography examination was performed to determine left ventricular function. RESULTS: The prevalence of on arrival high blood glucose among Javanese patients with acute coronary syndrome was considerably high (36%). On arrival high blood glucose was associated with acute heart failure (P < 0.001) and shock cardiogenic (P = 0.02). Heart rhythm disorders were higher in high blood glucose patients (P = 0.004). Left ventricular dysfunction was more prevalent in high blood glucose patients (P = 0.001) and ejection fraction was lower (P = 0.001). On arrival high blood glucose was independently associated with hospitalization adverse events (adjusted odds ratio = 2.3, 95% confidence interval: 1.1-4.9, P = 0.03) and hospital mortality (adjusted odds ratio = 6.9, 95% confidence interval: 1.2-38.6, P = 0.03). CONCLUSIONS: Our study suggests that on arrival high blood glucose among Javanese patients with acute coronary syndrome is considerably high and is associated with detrimental and fatal hospitalization outcomes.

Low serum albumin levels and in-hospital adverse outcomes in acute coronary syndrome.

Epidemiological studies have demonstrated an association between low serum albumin levels and coronary heart disease and mortality. Nevertheless, the impact of a low serum albumin level during acute coronary syndrome has not yet been established. The aim of the present study was to investigate whether low serum albumin levels are associated with adverse outcomes in acute coronary syndrome. We enrolled 82 consecutive patients with acute coronary syndrome from whom venous blood for serum albumin measurement was drawn immediately upon hospital admission. Thirty-five patients had a low albumin level (hypoalbuminemia) and 47 had a normal albumin level (normoalbuminemia). In-hospital adverse outcomes (death, acute heart failure, cardiogenic shock, and reinfarction) were recorded during hospitalization in the intensive coronary care unit. The results of our study showed that the incidence of in-hospital adverse outcomes was 43%, with death occurring in 8 patients (10%). In-hospital adverse outcomes occurred more frequently in patients presenting with hypoalbuminemia, whereas mortality did not differ significantly. Univariate analysis showed that hypoalbuminemia was associated with a 2.8-fold greater risk of developing adverse outcomes. This risk was greater in the subgroup of NSTEACS (5.4-fold increased risk), but not in those with STEMI. Adjustment with other covariates revealed that hypoalbuminemia did not predict independently in-hospital adverse outcomes. It interacted with other predictors, especially Killip class II-IV, which was consistently an independent predictor of in-hospital adverse outcomes.

Circulating soluble CD40 ligand mediates the interaction between neutrophils and platelets in acute coronary syndrome.

Following plaque rupture, activated platelet will induce subsequent inflammatory process including neutrophil recruitment. In vitro study demonstrated an interaction between neutrophils and platelets via a mechanism involving CD40-CD40 ligand. However, whether this mechanism exists in the clinical setting remains unknown. Fifty-four patients with acute myocardial infarction (AMI) and 25 with unstable angina of pain onset of < or = 24 h were enrolled consecutively. Acute myocardial infarction was diagnosed from three diagnostic criteria, i.e., anginal pain, electrocardiogram ST-T changes, and cardiac enzyme elevation. Unstable angina was diagnosed in patients without elevated cardiac enzymes. Peripheral venous blood was drawn at admission for routine blood count and soluble CD40 ligand (sCD40L) measurement. Neutrophil count was determined by an automated blood cell counter. Circulating sCD40L was measured using a standard enzyme-linked immunosorbent assay. Neutrophil count was significantly higher in AMI as compared with unstable angina (P < 0.001), whereas circulating sCD40L did not significantly differ. Despite marked elevation, no correlation was observed between neutrophil count and circulating sCD40L in AMI. Interestingly, we observed a strong and positive significant correlation between neutrophil count and circulating sCD40L level (r = 0.607, P = 0.002) in unstable angina. Circulating sCD40L is associated with neutrophil count and may mediate interaction between neutrophils and platelets in acute coronary syndrome, particularly in unstable angina.

Reductive gas-phase chemiluminescence and flow injection analysis for measurement of the nitric oxide pool in biological matrices.

There is growing evidence for nitric oxide (NO.) being involved in cell signaling and pathology. Much effort has been made to elucidate and characterize the different biochemical reaction pathways of NO.in vivo. However, a major obstacle in assessing the significance of nitrosated species and oxidized metabolites often remains: a reliable analytical technique for the detection of NO. in complex biological matrices. This chapter presents refined methodologies, such as chemiluminescence detection and flow injection analysis, compared with adequate sample processing procedures to reliably quantify and assess the circulating and resident NO(.) pool, consisting of nitrite, nitrate, nitroso, and nitrosylated species.

Positive effects of nitric oxide on left ventricular function in humans.

AIMS: The myocardial effect of tonically released nitric oxide (NO) in humans is still not known. We tested the hypothesis that low-dose NO exerts positive effects on left ventricular (LV) function. METHODS AND RESULTS: Twelve healthy volunteers, 26+/-4 years, were enrolled in this study. Magnetic resonance imaging was used to precisely measure the direct effects of NO on stroke volume index (SVI). The NO pool was monitored by chemiluminescence. We reduced endogenous NO levels with intravenous infusion of the NO synthase-inhibitor N(G)-monomethyl-l-arginine. Replenishment of the NO pool was achieved with the NO donor S-nitrosoglutathione (GSNO) (0.5 micromol iv). To differentiate load-dependent from the direct effects of NO on LV function, changes in SVI in response to GSNO were compared with changes in the NO-independent vasodilator dihydralazine (2.5 mg iv) at matched arterial pressure and heart rate. Inhibition of NO synthesis was followed by reduction in SVI. Subsequent replenishment of the circulating NO with GSNO significantly increased SVI (39+/-8 to 54+/-7 mL m(-2); P=0.001), whereas no significant changes were observed with the NO-independent vasodilator dihydralazine (39+/-8 to 46+/-8 mL m(-2); P=0.0626). CONCLUSION: Inhibition of endogenous NO release reduces, whereas replenishment with exogenous NO increases LV function, pointing towards a positive effect of tonically released NO on LV function in healthy humans.

Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans.

A reduced nitric oxide availability is a hallmark of endothelial dysfunction occurring early in atherosclerosis. Recently, we have shown that plasma nitrite mirrors acute changes in endothelial nitric oxide synthase activity in various mammals, including humans. Here, we examined the hypothesis that plasma nitrite levels are reduced in humans with endothelial dysfunction and the decrease is correlated with increasing numbers of cardiovascular risk factors (RF). Plasma nitrite concentrations were quantified by flow-injection analysis. The coefficient of variation for repeated measurements of plasma nitrite was <8%, and heart rate and blood pressure at the time of blood sampling had no significant effect on nitrite values measured (n=10). Baseline levels of plasma nitrite followed a normal distribution in each group studied and decreased progressively with increasing numbers of cardiovascular risk factors (n=351, p<0.001): 351+/-13 (0 RF), 261+/-10 (1 RF), 253+/-11 (2 RF), 222+/-18 (3 RF), and 171+/-29 nmol/L (4 RF). Intima media thickness (IMT) and flow-mediated dilation (FMD) were determined via ultrasound. Plasma nitrite and FMD levels were lower, whereas IMT was greater in individuals with endothelial dysfunction (n=12) compared to healthy volunteers (n=12). Nitrite correlated significantly with FMD (r=0.56, p<0.001) and inversely with IMT (r= -0.49, p<0.01). Plasma nitrite levels are reliably measurable in humans, indicate endothelial dysfunction, and correlate with cardiovascular risk factors. Future studies are necessary to identify the prognostic relevance of plasma nitrite determination in patients suffering from cardiovascular disease.

Red blood cells express a functional endothelial nitric oxide synthase.

The synthesis of nitric oxide (NO) in the circulation has been attributed exclusively to the vascular endothelium. Red blood cells (RBCs) have been demonstrated to carry a nonfunctional NO synthase (NOS) and, due to their huge hemoglobin content, have been assumed to metabolize large quantities of NO. More recently, however, RBCs have been identified to reversibly bind, transport, and release NO within the cardiovascular system. We now provide evidence that RBCs from humans express an active and functional endothelial-type NOS (eNOS), which is localized in the plasma membrane and the cytoplasm of RBCs. This NOS is regulated by its substrate L-arginine, by calcium, and by phosphorylation via PI3 kinase. RBC-NOS activity regulates deformability of RBC membrane and inhibits activation of platelets. The NOS-dependent conversion of L-arginine in RBCs is comparable to that of cultured human endothelial cells. RBCs in eNOS-/- mice in contrast to wild-type mice lack NOS protein and activity, strengthening the evidence of an eNOS in RBCs. These data show an eNOS-like protein and activity in RBCs serving regulatory functions in RBCs and platelets, which may stimulate new approaches in the treatment of NO deficiency states inherent to several vascular and hematologic diseases.

Enzyme-independent nitric oxide formation during UVA challenge of human skin: characterization, molecular sources, and mechanisms.

Many of the local UV-induced responses including erythema and edema formation, inflammation, premature aging, and immune suppression can be influenced by nitric oxide synthase (NOS)-produced NO which is known to play a pivotal role in cutaneous physiology. Besides NOS-mediated NO production, UV radiation might trigger an enzyme-independent NO formation in human skin by a mechanism comprising the decomposition of photo-reactive nitrogen oxides. Therefore, we have examined the chemical-storage forms of potential NO-generating agents, the mechanisms and kinetics of their decomposition, and their biological relevance. In normal human skin specimens we find nitrite and S-nitrosothiols (RSNO) at concentrations 25- or 360-fold higher than those found in plasma of healthy volunteers. UVA irradiation of human skin leads to high-output formation of bioactive NO due to photo-decomposition of RSNO and nitrite which represents the primary basis for NO formation during UVA exposure. Interestingly, reduced thiols strongly augment photo-decomposition of nitrite and are essential for maximal NO release. The enzyme-independent NO formation found in human skin opens a completely new field in cutaneous physiology and will extend our understanding of mechanisms contributing to skin aging, inflammation, and cancerogenesis.

Thiols enhance NO formation from nitrate photolysis.

Nitrate is generally considered an inert oxidative breakdown product of nitric oxide (NO). Whereas it has been shown that limited amounts of NO are produced during the photolysis of nitrate in aqueous solution, the photochemistry of nitrate in biological matrices such as plasma is unknown. We hypothesized that thiols, which are ubiquitously present in biological systems, may significantly enhance NO-quantum yields from nitrate photolysis. Exposure of fresh human plasma to high-intensity UV-light resulted in NO-formation (19 +/- 3 nmol/l/min) as measured by gas phase chemiluminescence, and this signal was almost completely abolished by the removal of plasma N-oxides (2 +/- 1 nmol/l/min). Reconstitution of NOx-depleted plasma samples with a physiological concentration of nitrate, but not nitrite, restored photolytic NO-generation to values comparable to naïve plasma. Addition of the thiol-reducing agent, dithiothreitol or the sulfhydryl-bearing amino acid, L-cysteine increased NO-formation above control levels. Thiol-blockade by either N-ethylmaleimide (NEM) or mercuric chloride (HgCl2) reduced basal NO formation from 19 +/- 3 to 7 +/- 2 and 4 +/- 1 nmol/l/min, respectively. Exposure of plasma to UV-light increased NO-adduct concentrations from 18 +/- 5 to 1662 +/- 658 nmol/l. Collectively, our results show that thiols facilitate photolytic conversion of nitrate to NO and NO-adducts such as S-nitrosothiols. This may lead to substantial overestimation of the latter when photolysis-based methodologies are used for their determination. Whether this novel reaction channel also has in vivo relevance remains to be investigated.

Plasma nitrosothiols contribute to the systemic vasodilator effects of intravenously applied NO: experimental and clinical Study on the fate of NO in human blood.

Higher doses of inhaled NO exert effects beyond the pulmonary circulation. How such extrapulmonary effects can be reconciled with the presumed short half-life of NO in the blood is unclear. Whereas erythrocytes have been suggested to participate in NO transport, the exact role of plasma in NO delivery in humans is not clear. Therefore, we investigated potential routes of NO decomposition and transport in human plasma. NO consumption in plasma was accompanied by a concentration-dependent increase in nitrite and S-nitrosothiols (RSNOs), with no apparent saturation limit up to 200 micro mol/L. The presence of red blood cells reduced the formation of plasma RSNOs. Intravenous infusion of 30 micro mol/min NO in healthy volunteers increased plasma levels of RSNOs and induced systemic hemodynamic effects at the level of both conduit and resistance vessels, as reflected by dilator responses in the brachial artery and forearm microvasculature. Intravenous application of S-nitrosoglutathione, a potential carrier of bioactive NO, mimicked the vascular effects of NO, whereas nitrite and nitrate were inactive. Changes in plasma nitrosothiols were correlated with vasodilator effects after intravenous application of S-nitrosoglutathione and NO. These findings demonstrate that in humans the pharmacological delivery of NO solutions results in the transport and delivery of NO as RSNOs along the vascular tree.