Forecasting the effect of water gastric emptying patterns on model drug release in an in vitro glass-bead flow-through system.

Oral solid dosage forms are most frequently administered with a glass of water which empties from the stomach relatively fast, but with a certain variability in its emptying kinetics. The purpose of this study was thus to simulate different individual water gastric emptying (GE) patterns in an in vitro glass-bead flow-through dissolution system. Further, the effect of GE on the dissolution of model drugs from immediate-release tablets was assessed by determining the amount of dissolved drug in the samples pumped out of the stomach compartment. Additionally, different HCl solutions were used as dissolution media to assess the effect of the variability of pH of the gastric fluid on the dissolution of three model drugs: paracetamol, diclofenac sodium, and dipyridamole. The difference in fast and slow GE kinetics resulted in different dissolution profiles of paracetamol in all studied media. For diclofenac sodium and dipyridamole tablets, the effect of GE kinetics was well observed only in media, where the solubility was not a limiting factor. Therefore, GE kinetics of co-ingested water influences the drug release from immediate-release tablets, however, in certain cases, other parameters influencing drug dissolution can partly or fully hinder the expression of this effect.

The Use of Global Sensitivity Analysis to Assess the Oral Absorption of Weakly Basic Compounds: A Case Example of Dipyridamole.

OBJECTIVE: To utilize the global system analysis (GSA) in oral absorption modeling to gain a deeper understanding of system behavior, improve model accuracy, and make informed decisions during drug development. METHODS: GSA was utilized to give insight into which drug substance (DS), drug product (DP), and/or physiological parameter would have an impact on peak plasma concentration (Cmax) and area under the curve (AUC) of dipyridamole as a model weakly basic compound. GSA guided the design of in vitro experiments and oral absorption risk assessment using FormulatedProducts v2202.1.0. The solubility and precipitation profiles of dipyridamole in different bile salt concentrations were measured. The results were then used to build a mechanistic oral absorption model. RESULTS: GSA warranted further investigation into the precipitation kinetics and its link to the levels of bile salt concentrations. Mechanistic modeling studies demonstrated that a precipitation-integrated modeling approach appropriately predicted the mean plasma profiles, Cmax, and AUC from the clinical studies. CONCLUSIONS: This work shows the value of GSA utilization in early development to guide in vitro experimentation and build more confidence in identifying the critical parameters for the mathematical models.

Vasodilatation stress cardiovascular magnetic resonance imaging: Feasibility, workflow and safety in a large prospective registry of more than 35,000 patients.

BACKGROUND: Cardiovascular magnetic resonance imaging (CMR) is an accurate technique for assessing ventricular function, myocardial perfusion and viability; its development remains limited mainly because of logistical and time constraints. Data regarding optimization of a dedicated stress CMR workflow are needed. AIMS: This study aimed to describe the optimization of a dedicated workflow, and to assess the feasibility and safety of stress CMR in a large registry of>35,000 patients. METHODS: A large single-centre French registry of vasodilator stress CMR included consecutive patients referred between 2008 and 2019 for the detection of inducible ischaemia. Stress CMR was performed at 1.5 Tesla using dipyridamole. Clinical and demographic data, test quality, CMR findings, haemodynamic data and complications were recorded prospectively. A locally optimized workflow was described and evaluated. RESULTS: Among the 35,862 patients referred for vasodilator stress CMR (mean age 68.9±11.8 years; 64.1% male), the stress CMR protocol was completed in 35,013 (97.6%) patients; 144 (0.3%) patients with missing baseline data were excluded. The mean examination duration was 27±5min, with image quality optimal in 90.8%, suboptimal in 7.1% and poor in 0.5% of cases. Images were diagnostic in 97.9% of patients. No patients died during or immediately after CMR. Fifty-six (0.16%) patients had severe complications. The incidence of non-severe complications was low (1.5%), whereas minor symptoms occurred frequently (35.5%). The presence of ischaemia was associated with a higher incidence of severe complications, non-severe complications and minor symptoms (all P<0.001). CONCLUSIONS: This single-centre prospective registry of>35,000 referral patients with known or suspected CAD showed that stress CMR was feasible in clinical routine practice, with high diagnostic image quality and an excellent safety profile. Inducible ischaemia was associated with severe complications, non-severe complications and minor symptoms.

Combined therapy of hypertensive nephropathy with ginkgo leaf extract and dipyridamole injection and antihypertensive drugs: A systematic review and meta-analysis.

BACKGROUND: In recent years, the incidence rate of hypertensive nephropathy has been increasing quickly, which has been a major threat to people's health. Renin-angiotensin-aldosterone system blockers have certain curative effects. However, there are some patients having serious adverse reactions, and the benefit population is limited, so the treatment of hypertensive renal damage is necessary to have beneficial supplement. More and more clinical studies have shown that ginkgo leaf extract and dipyridamole injection (GDI) combined with antihypertensive drugs has achieved good results in the treatment of hypertensive renal damage. It is supposed to be a supplementary treatment in hypertensive nephropathy. OBJECTIVES: To systematically assess the efficacy and safety of GDI combined with antihypertensive drugs on hypertensive renal injury. METHODS: Seven databases including PubMed, Cochrane Library, Embase, Wanfang database, China biomedical literature service system (Sino Med), VIP Chinese Sci-tech journal database (VIP), and China national knowledge internet (CNKI) were retrieved to collect randomized controlled trials (RCTs) in the experimental group containing combined therapy of hypertensive nephropathy with GDI and antihypertensive drugs. The retrieval time was from the establishment of database to July 8, 2020. Two researchers independently selected literature, extracted data, and evaluated the risk of bias in the study. The methodological quality was evaluated with Cochrane handbook and meta-analysis was performed with Stata 14.0 software. RESULTS: Eight studies were included in this study which involved 556 patients. The meta-analyses indicated that, compared with using antihypertensive drugs alone, combined treatment of GDI with antihypertensive drugs can decrease 24-hour urinary total protein (weighted mean difference [WMD] -0.61, 95% confidence interval [CI]: -0.82, -0.39; k = 6, P ≤ .001), blood urea nitrogen (WMD -1.27, 95% CI: -2.45, -0.10; k = 6, P = .033, serum creatinine (WMD -29.50, 95% CI: -56.44, -2.56; number of estimates [k] = 6, P = .032). CONCLUSIONS: Our meta-analyses showed that GDI combined with antihypertensive drugs can improve the renal function of hypertensive patients with renal injury.

A differential equation based modelling approach to predict supersaturation and in vivo absorption from in vitro dissolution-absorption system (idas2) data.

In vitro dissolution tests are widely used to monitor the quality and consistency of oral solid dosage forms, but to increase the physiological relevance of in vitro dissolution tests, newer systems combine dissolution and permeation measurements. Some of these use artificial membranes while others (e.g., in the in vitro dissolution absorption system 2; IDAS2), utilize cell monolayers to assess drug permeation. We determined the effect of the precipitation inhibitor Hypromellose Acetate Succinate (HPMCAS) on the supersaturation/permeation of Ketoconazole and Dipyridamole in IDAS2 and its effect on their absorption in rats. Thus the main objectives of this study were to determine: (1) whether dissolution and permeation data from IDAS2 could be used to predict rat plasma concentration using an absorption model and (2) whether the effect of the precipitation inhibitor HPMCAS on supersaturation and permeation in IDAS2 was correlated with its effect on systemic absorption in the rat. Predicted drug concentrations in rat plasma, generated using parameters estimated from IDAS2 dissolution/permeation data and a mathematical absorption model, showed good agreement with measured concentrations. While in IDAS2, the prolongation of Ketoconazole's supersaturation caused by HPMCAS led to higher permeation, which paralleled the higher systemic absorption in rats, Dipyridamole showed no supersaturation and, thus, no effect of HPMCAS in dissolution or permeation in IDAS2 and no effect on Dipyridamole absorption in rats. The ability of IDAS2 to detect supersaturation following a pH-shift supports the potential value of this system for studying approaches to enhance intestinal absorption through supersaturation and the accuracy of plasma concentration predictions in rats suggest the possibility of combining IDAS2 with absorption models to predict plasma concentration in different species.

Evaluation of the Presence and Functional Importance of Nucleoside Transporters in Lacrimal Gland for Tear Disposition of Intravenously Injected Substrate in Rabbits.

Purpose: Purpose of the current study was to assess the presence and functionality of the nucleoside transporters in the lacrimal gland for the tear disposition of its substrate given intravenously in rabbits.Materials and Methods: Rabbits were divided into two groups - control and blocker pretreated. The blocker pretreated group received 5 mg/kg of dipyridamole 30 min before ribavirin (substrate), which was given at a dose of 2.5 mg/kg. All the treatments were given intravenously. Blood and tear samples were collected at 5, 15, 30, 60, 90, 120, 180, 240, 300 and 360 min (n = 4; each time point) after substrate administration. Tear samples were collected on Schirmer's strips, and plasma was separated immediately after blood collection. All the samples were stored at -80°C until analysis by LC-MS/MS.Results: Plasma ribavirin concentration for blocker pretreated group showed significantly (p < .05) higher levels at 5, 15, 30, 60, 120, 180 and 300 min as compared to the control group. Similarly, tear ribavirin concentration for blocker pretreated group also showed a significant (p < .05) increase at 5, 15, 60, 90, 180, 240 and 300 min compared to the control group. Plasma and tear AUC(0-6) for blocker pretreated group was 1.7 (p < .001) and 2.42 (p < .001) folds higher in a significant manner as compared to the control group, respectively. Percentage penetration of ribavirin from plasma to tears was also different between control and blocker pretreated group. Permeation ratio of ribavirin from plasma to tear for blocker pretreated group was found to be 1.4-folds higher in a significant (p < .05) manner.Conclusion: It is evident from the results that nucleoside transporters are present in lacrimal gland. The blocker treatment induced increase in tear transport of ribavirin indicates the possibility of the presence of nucleoside transporters on the apical side of lacrimal acinar cells in the uptake position.

Long-term prognostic value of stress perfusion cardiovascular magnetic resonance in patients without known coronary artery disease.

BACKGROUND: To assess the incremental long-term prognostic value of vasodilator stress perfusion cardiovascular magnetic resonance (CMR) in patients without known coronary artery disease (CAD). METHODS: Between 2010 and 2011, consecutive patients with cardiovascular risk factors without known CAD referred for stress CMR were followed for the occurrence of major adverse cardiac events (MACE), defined by cardiovascular mortality or recurrent non-fatal myocardial infarction (MI). Uni- and multivariable Cox regressions were performed to determine the prognostic value of ischemia and unrecognized MI defined by sub-endocardial or transmural late gadolinium enhancement (LGE). RESULTS: Among 2,295 patients without known CAD, 2058 (89.7%) (71.2 ± 12.5 years; 37.5% males) completed the follow-up (median [IQR]: 8.3 [7.3-8.7] years), and 203 had MACE (9.9%). Using Kaplan-Meier analysis, ischemia and unrecognized MI were associated with MACE (hazard ratio, HR: 4.64 95% CI: 3.69-6.17 and HR: 2.88; 95% CI: 2.08-3.99, respectively; both p < 0.001). In multivariable stepwise Cox regression, ischemia and unrecognized MI were independent predictors of MACE (HR = 3.71; 95% CI 2.73-5.05, p < 0.001 and HR = 1.73; 95% CI 1.22-2.45, p = 0.002; respectively) and cardiovascular mortality (HR: 3.13; 95% CI: 2.17-4.51, p < 0.001 and HR = 1.73; 95% CI 1.15-2.62, p = 0.009; respectively). The addition of ischemia and unrecognized MI led to an improved model discrimination for MACE (change in C statistic from 0.61 to 0.72; NRI = 0.431; IDI = 0.053). CONCLUSIONS: Inducible ischemia and unrecognized MI identified by stress CMR have incremental long term prognostic value for the incidence of MACE in patients without known CAD over traditional risk factors and left ventricular ejection fraction.

Prognostic value of stress cardiovascular magnetic resonance in asymptomatic patients with known coronary artery disease.

BACKGROUND: Several studies have established the prognostic value of vasodilator stress cardiovascular magnetic resonance (CMR) in broad population of patients with suspected or known coronary artery disease (CAD), but this specific population of asymptomatic patients with known CAD have never been formally evaluated. To assess the long-term prognostic value of vasodilator stress perfusion CMR in asymptomatic patients with obstructive CAD. METHODS: Between 2009 and 2011, consecutive asymptomatic patients with obstructive CAD referred for vasodilator stress CMR were followed for the occurrence of major adverse cardiovascular events (MACE), defined by cardiovascular mortality or recurrent non-fatal myocardial infarction (MI). Uni- and multivariable Cox regressions were performed to determine the prognostic value of myocardial ischemia and myocardial infarction defined by late gadolinium enhancement (LGE) with ischemic pattern. RESULTS: Among 1529 asymptomatic patients with obstructive CAD, 1342 (87.8%; 67.7 ± 10.5 years, 82.0% males) completed the follow-up (median 8.3 years), and 195 had MACE (14.5%). Patients without stress-induced myocardial ischemia had a low annualized rate of MACE (2.4%), whereas the annualized rate of MACE was higher for patients with mild, moderate, or severe ischemia (7.3%, 16.8%, and 42.2%, respectively; ptrend < 0.001). Using Kaplan-Meier analysis, myocardial ischemia and LGE were associated with MACE (hazard ratio, HR 2.52; 95% CI 1.90-3.34 and HR 2.04; 95% CI 1.38-3.03, respectively; both p < 0.001). In multivariable stepwise Cox regression, myocardial ischemia and LGE were independent predictors of MACE (HR 2.80 95% CI 2.10-3.73, p < 0.001 and HR 1.51; 95% CI 1.01-2.27, p = 0.045; respectively). The addition of myocardial ischemia and LGE led to improved model discrimination for MACE (change in C statistic from 0.61 to 0.68; NRI = 0.207; IDI = 0.021). CONCLUSIONS: Vasodilator stress CMR-induced myocardial ischemia and LGE are good long-term predictors for the incidence of MACE in asymptomatic patients with obstructive CAD.

Stomach pH before vs. after different bariatric surgery procedures: Clinical implications for drug delivery.

Stomach pH may vary following bariatric surgery, with implications for drug delivery/bioavailability. Yet, this parameter has not been studied. In this work, gastric content was aspirated from patients before, immediately after, and the day after different bariatric procedures, and pH was immediately measured. Compared to pre-surgery (1.8), pH was increased one day after one-anastomosis gastric bypass (OAGB) and sleeve gastrectomy (LSG) by 3-4 pH units; pH immediately after these procedures was in between the other 2 time points. Post-OAGB pH was significantly higher than post-LSG (6.4 and 4.9, respectively). Prior adjustable gastric band did not significantly alter baseline pH. We then performed drug dissolution studies of the antiplatelet drugs dipyridamole and aspirin, mimicking pre-surgery, post-LSG and post-OAGB conditions, implementing our pH results and other relevant physiological parameters. Dipyridamole, a weak base, completely dissolved (100% of dose) under pre-surgery conditions, while dissolution was hampered under post-LSG (5%) and post-OAGB (0.25%) conditions, due to solubility limit. Aspirin was not released from enteric-coated tablet under pre-surgery or post-LSG gastric conditions, however, >75% dissolved within 15 min under post-OAGB gastric conditions, indicating potential failure of enteric coating, depending on the bariatric procedure. In conclusion, special care should be taken when using pH-dependent drugs and drug products after bariatric surgery, and the use of pH-independent formulations should be preferred. Overall, this research revealed the interim gastric pH after different bariatric procedures, and potentially important effects on post-bariatric oral drug delivery and treatment.

Practical instructions for using drugs in CT and MR cardiac imaging.

The progressive increase in numbers of noninvasive cardiac imaging examinations broadens the spectrum of knowledge radiologists are expected to acquire in the management of drugs during CT coronary angiography (CTCA) and cardiac MR (CMR) to improve image quality for optimal visualization and assessment of the coronary arteries and adequate MR functional analysis. Aim of this review is to provide an overview on different class of drugs (nitrate, beta-blockers, ivabradine, anxiolytic, adenosine, dobutamine, atropine, dipyridamole and regadenoson) that can be used in CTCA and CMR, illustrating their main indications, contraindications, efficacy, mechanism of action, metabolism, safety, side effects or complications, and providing advices in their use.

Myocardial strain indices and coronary flow reserve are only mildly affected in healthy hypertensive patients.

To investigate changes in two-dimensional myocardial strain echocardiography (2DSTE) indices following a dipyridamole stress test (DIPSE) in relatively healthy hypertensive patients and healthy controls. Forty-seven male hypertensive patients (aged 57±9 years) with normal ejection fraction and without left ventricular (LV) hypertrophy and 20 healthy male subjects were studied with conventional and 2DSTE echocardiography at rest and post DIPSE. Coronary flow reserve (CFR) in the left anterior descending artery following DIPSE was also evaluated. Global longitudinal strain (GLS) and TWIST were higher while UNTWIST rate was lower in hypertensives versus controls (p < 0.05 for all); TWIST remained higher in hypertensives (p = 0.021) after adjustment for differences in age and body mass index (BMI) between the groups. CFR was higher in controls compared to hypertensives even after adjustment for confounders (4.14 vs. 2.53, p = 0.001). DIPSE-induced changes did not differ between the groups after adjustment for age and BMI (p > 0.05 for all). DIPSE-induced improvement in GLS was associated with higher CFR only in hypertensive patients (r - 0.372, p = 0.010). The current study showed that well controlled hypertensive patients have only mild echocardiographic differences compared to controls; some of these differences appear to depend on age and BMI. A 'hyper-rotation' phenomenon (i.e. higher TWIST) early in hypertension may be a compensatory mechanism to preserve global systolic LV function. Coronary microcirculatory function was impaired in hypertensive patients, albeit within normal range, and was associated with DIPSE-induced changes in myocardial long-axis systolic function.

Análise Comparativa do Padrão de Fluxo de Artérias Coronárias das Hipertrofias Miocárdicas Secundárias e por Mutação Sarcomérica / Comparative Analysis of the Coronary Arteries Flow Pattern in Secondary Myocardial Hypertrophies and by Sarcomeric Mutation

Fundamento: O fluxo coronariano com predomínio diastólico aumenta duas a cinco vezes na hiperemia, mediada por vasodilatação (reserva de fluxo coronariano), podendo, na hipertrofia, ocorrer isquemia relativa. Na hipertrofia secundária, o fluxo em repouso torna-se isquêmico pelo aumento da demanda. Na cardiomiopatia hipertrófica com fibrose perivascular, há funcionalização de vasos colaterais, para aumentar a irrigação dos segmentos hipertrofiados. Objetivo: Determinar o padrão do fluxo coronariano em pacientes com hipertrofia secundária e cardiomiopatia hipertrófica, avaliando a reserva de fluxo coronariano. Métodos: Avaliamos o fluxo coronariano em 34 pacientes com hipertrofia secundária, em 24 com cardiomiopatia hipertrófica e em 16 controles. A artéria descendente anterior foi detectada com Doppler transtorácico com calibração adequada do equipamento. Nos grupos controle e com hipertrofia secundária, foi calculada a reserva de fluxo coronariano com dipiridamol (0,84 mg/kg) endovenoso. O mesmo procedimento foi realizado em seis pacientes do grupo com cardiomiopatia hipertrófica, nos quais também foi avaliado o fluxo das colaterais da região hipertrófica. Os dados foram comparados por variância com significância de 5%. Resultados: Na hipertrofia secundária, houve aumento do índice de massa e, na cardiomiopatia hipertrófica, predominou o aumento da espessura relativa. A fração de ejeção e a disfunção diastólica foram maiores no grupo com cardiomiopatia hipertrófica. A reserva de fluxo coronariano foi menor no grupo com cardiomiopatia hipertrófica, sendo detectado, também, fluxo de colaterais com redução da reserva de fluxo coronariano. Conclusão: A análise da circulação coronariana com Doppler transtorácico é possível em indivíduos normais e hipertróficos. Pacientes com hipertrofia secundária e cardiomiopatia hipertrófica apresentam diminuição da reserva de fluxo coronariano, e aqueles com cardiomiopatia hipertrófica mostram fluxo de vasos colaterais dilatados observados na região hipertrófica, com diminuição da reserva de fluxo coronariano.(AU)

Background: Coronary flow with a diastolic predominance increases two to five times in hyperemia, mediated by vasodilation (coronary flow reserve, CFR) and, in hypertrophy, relative ischemia may occur. In secondary hypertrophy (LVH), the flow, normal at rest, becomes ischemic due to increased demand. In hypertrophic cardiomyopathy (HCM) with perivascular fibrosis, collateral vessels appear to increase the irrigation of hypertrophied segments. Objective: To determine the coronary flow pattern in patients with secondary hypertrophy and hypertrophic cardiomyopathy, evaluating the coronary flow reserve. Methods: Coronary flow was evaluated in 34 patients with secondary hypertrophy, 24 with hypertrophic cardiomyopathy and in 16 controls. The anterior descending artery was detected with transthoracic Doppler with adequate equipment calibration. In the hypertrophic cardiomyopathy group, the flow of collaterals from the hypertrophic region was evaluated. In the control and secondary hypertrophy groups and in six patients in the hypertrophic cardiomyopathy group, the intravenous dipyridamole (0.84 mg) coronary flow reserve was calculated. The data were compared by variance with a significance of 5%Results: In secondary hypertrophy there was an increase in mass index and blood pressure, and in hypertrophic cardiomyopathy an increase in relative thickness predominated. Ejection fraction and diastolic dysfunction were higher in the hypertrophic cardiomyopathy group. The coronary flow reserve was lower in the hypertrophic cardiomyopathy group, and flow of collaterals was also detected, with a reduction in the coronary flow reserve. Conclusion: the analysis of coronary circulation with transthoracic Doppler is possible in normal and hypertrophic individuals. Patients with secondary hypertrophy and hypertrophic cardiomyopathy have a decrease in the coronary flow reserve, and patients with hypertrophic cardiomyopathy show a hyper flow of dilated collateral vessels observed in the hypertrophic region, with a decrease in the coronary flow reserve.(AU)

Prevalence and prognostic impact of nonischemic late gadolinium enhancement in stress cardiac magnetic resonance.

AIM: To assess the prevalence and prognostic significance of NI-LGE in patients undergoing stress-CMR. METHODS: Stress-CMR with either dipyridamole or adenosine was performed in 283 patients (228 men, 81%) including perfusion imaging, wall motion evaluation and LGE. Follow-up was completed in all enrolled patients (median time: 1850 days; interquartile range: 1225-2705 days). Composite endpoint included cardiac death, ventricular tachycardia, myocardial infarction, stroke, hospitalization for cardiac cause and coronary revascularization performed beyond 90 days from stress-CMR scans. RESULTS: One hundred and twelve patients (40%) had negative LGE (no-LGE), 140 patients (49%) I-LGE and 31 patients (11%) NI-LGE. Twenty-five events occurred in the no-LGE group, 68 in I-LGE and 11 in the NI-LGE group. On survival curves, patients with NI-LGE had worse prognosis than patients with no-LGE regardless of the presence of inducible perfusion defects. No significant prognostic differences were found between I-LGE and NI-LGE. CONCLUSION: NI-LGE can be detected in 11% of patients during stress-CMR providing a diagnosis of nonischemic cardiac disease. Patients with NI-LGE have worse prognosis than those with no-LGE.

Safety and Prognostic Value of Vasodilator Stress Cardiovascular Magnetic Resonance in Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF; heart failure with reduced left ventricular ejection fraction <40%) referred for stress cardiovascular magnetic resonance (CMR) may have a less optimal hemodynamic response to intravenous vasodilator. The aim was to assess the prognostic value of vasodilator stress perfusion CMR in patients with HFrEF. METHODS: Between 2008 and 2018, consecutive patients with HFrEF defined by left ventricular ejection fraction <40% prospectively referred for vasodilator stress perfusion CMR were followed for the occurrence of major adverse cardiovascular events (MACE), defined by cardiovascular death or nonfatal myocardial infarction. Univariable and multivariable Cox regressions were performed to determine the prognostic value of inducible ischemia or late gadolinium enhancement by CMR. RESULTS: Of 1053 patients with HFrEF (65±11 years, median [interquartile range] left ventricular ejection fraction 38.7% [37.2-39.0]), 1018 (97%) completed the CMR protocol and 950 (93%) completed the follow-up (median [interquartile range], 5.6 [3.6-7.3] years); 117 experienced a MACE (12.3%). Stress CMR was well tolerated without any adverse events. Patients without ischemia or late gadolinium enhancement experienced a lower annual event rate of MACE (1.8%) than those with both ischemia and late gadolinium enhancement (12.0%; P<0.001). Using Kaplan-Meier analysis, inducible ischemia and late gadolinium enhancement were significantly associated with the occurrence of MACE (hazard ratio, 2.46 [95% CI, 1.69-3.60]; and hazard ratio, 2.92 [95% CI, 1.77-4.83], respectively, both P<0.001). In multivariable Cox regression, inducible ischemia was an independent predictor of a higher incidence of MACE (hazard ratio, 2.26 [95% CI, 1.52-3.35]; P<0.001). CONCLUSIONS: Stress CMR is safe and has a good discriminative prognostic value to predict the occurrence of MACE in patients with HFrEF.

Increased symmetric dimethylarginine, but not asymmetric dimethylarginine, concentrations are associated with transient myocardial ischemia and predict outcome.

OBJECTIVE: Asymmetric and symmetric dimethylarginines (ADMA and SDMA) are endothelial dysfunction markers. ADMA inhibits synthesis of nitric oxide. We aimed to analyze both markers in patients with coronary artery disease (CAD) who were referred for stress/rest myocardial perfusion scintigraphy (MPS). METHODS: All patients underwent a 2-day dipyridamole (DP) stress/rest protocol. Thereafter, patients with transient myocardial perfusion abnormality were followed up and their coronary blood flow was quantitatively assessed. Venous blood was taken before and after DP stress to measure markers. RESULTS: Baseline ADMA and SDMA concentrations were significantly higher in patients with CAD compared with healthy subjects. Pre- and post-stress SDMA concentrations were significantly higher in patients with transient myocardial perfusion abnormality compared with those with negative MPS results. However, ADMA and L-arginine concentrations were not significantly different between the two groups. None of the markers were significantly different between patients with angiographically proven low coronary flow and those with normal coronary flow. Pre-stress SDMA concentrations were an independent predictor of cardiovascular mortality during a 8-year follow-up. CONCLUSIONS: Elevated serum SDMA concentrations may be helpful for selecting high-risk patients with CAD if there is any doubt in interpreting MPS. SDMA concentrations may also predict cardiovascular outcome.

Prognostic value of heart rate reserve is additive to coronary flow velocity reserve during dipyridamole stress echocardiography.

BACKGROUND: During dipyridamole stress echocardiography (SE), a blunted heart rate reserve (HRR) is a prognostically unfavourable sign of cardiac autonomic dysfunction. AIM: To assess the prognostic meaning of HRR and coronary flow velocity reserve (CFVR). METHODS: The study group comprised 2149 patients (1236 men; mean age 66±12 years) with suspected (n=1280) or known (n=869) coronary artery disease and without inducible regional wall motion abnormalities (RWMA) during dipyridamole SE (0.84mg/kg in 6min). We assessed CFVR of the left anterior descending artery with pulsed-wave Doppler as the ratio between hyperaemic peak and basal peak diastolic flow velocities (abnormal value≤2.0). HRR was calculated as the peak/resting ratio of heart rate from a 12-lead electrocardiogram (abnormal value≤1.22). All patients were followed up. RESULTS: CFVR and HRR were abnormal in 520 (24%) and 670 (31%) patients, respectively. There was a positive linear correlation between CFVR and HRR (r=0.30; P<0.0001). During a median follow-up of 22 months (1st quartile 12 months, 3rd quartile 35 months), 75 (6%) patients died. The annual mortality was 1.6% in the overall population, 0.5% in the 1224 (57%) patients with normal CFVR and HRR, 1.7% in the 405 (19%) patients with abnormal HRR only, 3.6% in the 255 (12%) patients with abnormal CFVR only, and 6.2% in the 265 (12%) patients with abnormal CFVR and HRR. CONCLUSIONS: HRR is weakly related to CFVR, and a blunted HRR usefully complements RWMA and CFVR for prediction of outcome with dipyridamole SE. The patient without inducible RWMA is still at intermediate risk, but the risk is low with concomitant preserved CFVR, and very low with concomitant normal HRR.

Impact of dipyridamole on adenosine dosing in pediatric and young adult patients after heart transplantation.

BACKGROUND: Relative contraindications to adenosine use have included heart transplant and dipyridamole. We previously demonstrated the safety and efficacy of adenosine-induced atrioventricular (AV) block in healthy young heart transplant recipients while suspending dipyridamole therapy (dual antiplatelet agent). This prospective follow-up study evaluated the safety and efficacy of adenosine use in the same cohort of heart transplant recipients while on dipyridamole. METHODS: Adenosine was incrementally dosed until AV block occurred (maximum 200 mcg/kg up to 12 mg). The primary outcome was clinically significant asystole (≥12 seconds). Secondary outcomes included maximal adenosine dose, AV block duration, dysrhythmias, and clinical symptoms. Outcomes were compared to the parent study. RESULTS: Thirty of 39 eligible patients (5-24 years) were tested. No patient (0%, CI 0%-8%) experienced clinically significant asystole. AV block occurred in 29/30 patients (97%, CI 86%-100%). The median dose causing AV block was 50mcg/kg (vs 100 mcg/kg off dipyridamole; P = .011). Seventeen patients (57%, CI 39%-72%) required less adenosine to achieve AV block on dipyridamole; six (20%) required more. AV block occurred at doses ≥25 mcg/kg in all patients. In pairwise comparison to prior testing off dipyridamole, no significant change occurred in AV block duration, frequency of cardiac ectopy, or incidence of reported symptoms. No atrial fibrillation/flutter occurred. CONCLUSIONS: AV block often occurs at twofold lower adenosine doses in healthy young heart transplant recipients taking oral dipyridamole, compared with previous testing of this cohort off dipyridamole. Results suggest that initial dosing of 25 mcg/kg (maximum 0.8 mg) with stepwise escalation poses low risk of prolonged asystole on dipyridamole.

Ultrasonography after pharmacological stimulation of erection for the diagnosis and therapeutic follow-up of erectile dysfunction due to cavernovenous leakage.

The goal of this work was to demonstrate that Doppler ultrasound (DUS) after pharmacological stimulation of erection (PSE) can be used to evaluate the presence and intensity of a cavernovenous leak (CVL) suspected in erectile dysfunction (ED) patients. The study was built around 50 DUS-PSE exams of penile arteries and veins, which were carried out 3, 5, 10 and 20minutes after pharmacological stimulation. Measured parameters were end diastolic velocity of the cavernous arteries and mean velocity of the deep penile vein and/or penile superficial veins. A score from 0 to 3 was attributed to each according to the recorded velocities. A final score from 0 to 9 was established by adding the three values: patients quoting 0 and 1 were classified as "no leak" (n=8); from 2 to 9 (n=42) as "leaking". Penile computed tomography (CT-scan) under identical pharmacological stimulation identified the cavernovenous leak to be compared with the DUS-PSE results, which were valid in 47 cases (94%), with 97.6% sensitivity and 77.7% specificity. The kappa correlation coefficient for CT-scan diagnosis of suspected CVL was 0.7875 (P<0.001). In addition, we found that end diastolic velocity in the cavernous artery, considered up until now as the gold standard in cases of suspected CVL was insufficient (negative predictive value=47%). In addition to its well-known diagnostic value regarding ED of arterial origin, DUS-PSE is an excellent screening test for CVL, especially in young patients without vascular risk factors who are resistant to medical treatments. For those with well-established CVL, confirmation by CT-scan to discuss possible surgery should be the next step. Moreover, DUS-PSE is useful in postoperative monitoring.

Comparison of Antiplatelet Therapies for Prevention of Patent Foramen Ovale-Associated Stroke.

AIMS: The REDUCE study demonstrated a reduction in the risk of recurrent stroke with patent foramen ovale closure and antiplatelet therapy compared to antiplatelet therapy alone. The clinicians were allowed to choose among aspirin, clopidogrel, or aspirin/dipyridamole with the expectation that all antiplatelet therapies would have similar efficacy in this population. We tested that presumption by comparing recurrent stroke rates among antiplatelet agents within the control arm of the trial. METHODS: We evaluated patients in REDUCE study who were randomized to the medical arm. The primary endpoint for this analysis was freedom from clinical ischemic stroke through at least 2 years of follow-up, to a maximum of 5 years. In the primary analysis, antiplatelet treatment was defined as the agent during the week prior to a recurrent stroke or last known contact. RESULTS: Of 223 patients in the medical treatment arm, the initial agent was aspirin 52%, clopidogrel 30%, and aspirin/dipyridamole 12%. Patients treated with aspirin were similar to those treated with alternatives, but were more likely to be enrolled in the United States. The last reported agent was aspirin alone in 55%, clopidogrel alone in 31%, aspirin/dipyridamole in 7%, and other/nothing/missing in 7%. Recurrent stroke rates were similar for all 3 antiplatelet regimens in unadjusted and adjusted analyses, with no overall difference among agents (P= .17). CONCLUSIONS: Among patients with patent foramen ovale-associated stroke who were managed medically, there were no differences among antiplatelet agents in the risk of recurrent stroke, though confidence intervals were wide.

Bone Tissue Engineering in the Growing Calvaria Using Dipyridamole-Coated, Three-Dimensionally-Printed Bioceramic Scaffolds: Construct Optimization and Effects on Cranial Suture Patency.

BACKGROUND: Three-dimensionally-printed bioceramic scaffolds composed of ß-tricalcium phosphate delivering the osteogenic agent dipyridamole can heal critically sized calvarial defects in skeletally mature translational models. However, this construct has yet to be applied to growing craniofacial models. In this study, the authors implanted three-dimensionally-printed bioceramic/dipyridamole scaffolds in a growing calvaria animal model and evaluated bone growth as a function of geometric scaffold design and dipyridamole concentration. Potential adverse effects on the growing suture were also evaluated. METHODS: Bilateral calvarial defects (10 mm) were created in 5-week-old (approximately 1.1 kg) New Zealand White rabbits (n = 16 analyzed). Three-dimensionally-printed bioceramic scaffolds were constructed in quadrant form composed of varying pore dimensions (220, 330, and 500 µm). Each scaffold was coated with collagen and soaked in varying concentrations of dipyridamole (100, 1000, and 10,000 µM). Controls consisted of empty defects. Animals were killed 8 weeks postoperatively. Calvariae were analyzed using micro-computed tomography, three-dimensional reconstruction, and nondecalcified histologic sectioning. RESULTS: Scaffold-induced bone growth was statistically greater than bone growth in empty defects (p = 0.02). Large scaffold pores, 500 µm, coated in 1000 µM dipyridamole yielded the most bone growth and lowest degree of scaffold presence within the defect. Histology showed vascularized woven and lamellar bone along with initial formation of vascular canals within the scaffold lattice. Micro-computed tomographic and histologic analysis revealed patent calvarial sutures without evidence of ectopic bone formation across all dipyridamole concentrations. CONCLUSION: The authors present an effective pediatric bone tissue-engineering scaffold design and dipyridamole concentration that is effective in augmentation of calvarial bone generation while preserving cranial suture patency.