Noninvasive assessment of human microvascular function in health and disease using incident dark-field microscopy.

Reduced peripheral microvascular reactivity is associated with an increased risk for major adverse cardiac events (MACEs). Tools for noninvasive assessment of peripheral microvascular function are limited, and existing technology is poorly validated in both healthy populations and patients with cardiovascular disease (CVD). Here, we used a handheld incident dark-field imaging tool (CytoCam) to test the hypothesis that, compared with healthy individuals (no risk factors for CVD), subjects formally diagnosed with coronary artery disease (CAD) or those with ≥2 risk factors for CAD (at risk) would exhibit impaired peripheral microvascular reactivity. A total of 17 participants (11 healthy, 6 at risk) were included in this pilot study. CytoCam was used to measure sublingual microvascular total vessel density (TVD), perfused vessel density (PVD), and microvascular flow index (MFI) in response to the topical application of acetylcholine (ACh) and sublingual administration of nitroglycerin (NTG). Baseline MFI and PVD were significantly reduced in the at-risk cohort compared with healthy individuals. Surprisingly, following the application of acetylcholine and nitroglycerin, both groups showed a significant improvement in all three microvascular perfusion parameters. These results suggest that, despite baseline reductions in both microvascular density and perfusion, human in vivo peripheral microvascular reactivity to both endothelial-dependent and -independent vasoactive agents remains intact in individuals with CAD or multiple risk factors for disease.NEW & NOTEWORTHY To our knowledge, this is the first study to comprehensively characterize in vivo sublingual microvascular structure and function (endothelium-dependent and -independent) in healthy patients and those with CVD. Importantly, we used an easy-to-use handheld device that can be easily translated to clinical settings. Our results indicate that baseline microvascular impairments in structure and function can be detected using the CytoCam technology, although reactivity to acetylcholine may be maintained even during disease in the peripheral microcirculation.

Role of acetylcholine spasm provocation test as a pathophysiological assessment in nonobstructive coronary artery disease.

Coronary angiography (CAG) sometimes shows nonobstructive coronary arteries in patients with suspected angina or acute coronary syndrome (ACS). The high prevalence of nonobstructive coronary artery disease (CAD) in those patients has recently been reported not only in Japan but also in Western countries, and is clinically attracting attention. Coronary spasm is considered to be one of the leading causes of both suspected stable angina and ACS with nonobstructive coronary arteries. Coronary spasm could also be associated with left ventricular dysfunction leading to heart failure, which could be improved following the administration of calcium channel blockers. Because we rarely capture spontaneous attacks of coronary spasm with electrocardiograms or Holter recordings, an invasive diagnostic modality, acetylcholine (ACh) provocation test, can be useful in detecting coronary spasm during CAG. Furthermore, we can use the ACh-provocation test to identify high-risk patients with coronary spasm complicated with organic coronary stenosis, and then treat with intensive care. Nonobstructive CAD includes not only epicardial coronary spasm but also microvascular spasm or dysfunction that can be associated with recurrent anginal attacks and poor quality of life. ACh-provocation test could also be helpful for the assessment of microvascular spasm or dysfunction. We hope that cardiologists will increasingly perform ACh-provocation test to assess the pathophysiology of nonobstructive CAD.

Clinical assessment of adenosine stress and rest cardiac magnetic resonance T1 mapping for detecting ischemic and infarcted myocardium.

Cardiac magnetic resonance (CMR) spin-lattice relaxation time (T1) may be influenced by pathologic conditions due to changes in myocardial water content. We aimed to validate the principle and investigate T1 mapping at rest and adenosine stress to differentiate ischemic and infarcted myocardium from controls. Patients with suspected coronary artery disease who underwent CMR were prospectively recruited. Native rest and adenosine stress T1 maps were obtained using standard modified Look-Locker Inversion-Recovery technique. Among 181 patients included, T1 values were measured from three groups. In the control group, 72 patients showed myocardium with a T1 profile of 1,039 ± 75 ms at rest and a significant increase during stress (4.79 ± 3.14%, p < 0.001). While the ischemic (51 patients) and infarcted (58 patients) groups showed elevated resting T1 compared to controls (1,040 ± 90 ms for ischemic; 1,239 ± 121 ms for infarcted, p < 0.001), neither of which presented significant T1 reactivity (1.38 ± 3.02% for ischemic; 1.55 ± 5.25% for infarcted). We concluded that adenosine stress and rest T1 mapping may be useful to differentiate normal, ischemic and infarcted myocardium.

An intact animal model for the assessment of coronary blood flow regulation "Coronary blood flow regulation".

Coronary blood flow adapts to metabolic demand ("metabolic regulation") and remains relatively constant over a range of pressure changes ("autoregulation"). Coronary metabolic regulation and autoregulation are usually studied separately. We developed an intact animal experimental model to explore both regulatory mechanisms of coronary blood flow. Coronary pressure and flow-velocities were measured in four anesthetized and closed-chest pigs using an intracoronary Doppler wire. Metabolic regulation was assessed by coronary flow reserve defined as the ratio between the maximally vasodilated and the basal flow, with hyperemia achieved using intracoronary administration of adenosine (90 µg) or bradykinin (10-6  M) as endothelium-independent and -dependent vasodilators respectively. For both vasodilators, we found a healthy coronary flow reserve ≥ 3.0 at baseline, which was maintained at 2.9 ± 0.2 after a 6-hr period. Autoregulation was assessed by the lower breakpoint of coronary pressure-flow relationships, with gradual decrease in coronary pressure through the inflation of an intracoronary balloon. We found a lower limit of autoregulation between 42 and 55 mmHg, which was stable during a 6-hr period. We conclude that this intact animal model is adequate for the study of pharmacological interventions on the coronary circulation in health and disease, and as such suitable for preclinical drug studies.

Assessment of tissue perfusion and vascular function in mice by scanning laser Doppler perfusion imaging.

Post-occlusive reactive hyperemia (PORH) is a key feature of physiological vasomotion to appropriately match the supply/demand ratio of tissues. This adaptive mechanism is severely disturbed in endothelial dysfunction with a reduced flow-mediated dilation (FMD). Reduced PORH and FMD are powerful prognostic risk factors in cardiovascular diseases. While these parameters are frequently determined in human beings, comparable methods applicable to mouse models are sparse. We aimed to evaluate the applicability and accuracy of scanning laser Doppler perfusion imaging (LDPI) to measure PORH in the mouse hindlimb. Changes in mean perfusion in response to vasoactive drugs and PORH (assessed by scanning LDPI) were compared with changes in diameter and blood flow in the femoral artery, as assessed by high-resolution ultrasound. We found that the measured LDPI signal significantly correlated with changes of inflow into the femoral artery. Vasodilation induced by administration of nitroglycerine and acetylcholine increased vessel diameter, blood flow and mean perfusion, while vasoconstriction following administration of epinephrine decreased all three parameters. PORH was induced by temporal occlusion of the femoral artery with an external cuff. During occlusion, mean perfusion decreased to a condition of zero-perfusion and release of the cuff induced an immediate increase in blood flow that was followed by femoral artery dilation driving PORH/perfusion. Surgical removal of the femoral artery decreased mean perfusion to a zero-perfusion level and fully abolished PORH. Importantly, the measurement of the PORH response by scanning LDPI is highly reproducible as determined by repeated measurements and intra/interobserver variation analysis. Last, we found that the PORH response was dependent on nitric oxide synthase and cyclooxygenase and declined with age. Thus, we here provide novel and robust non-invasive methods to serially measure tissue perfusion at baseline and during physiological and pharmacological modulation of vasomotor tone in the hindlimb of mice. The application of these LDPI scanning and ultrasound-based methods may be useful for testing the effects of drugs affecting vasomotor function or future elucidation of mechanisms leading to vasomotor dysfunction in mice in vivo.

[Invasive functional assessment of coronary artery stenosis using fractional flow reserve]. / Valutazione funzionale invasiva delle stenosi coronariche mediante riserva frazionale di flusso coronarico.

The presence of myocardial ischemia significantly affects prognosis of patients with coronary artery disease. The fractional flow reserve (FFR) allows interventional cardiologists to evaluate whether an equivocal coronary artery stenosis is associated or not with myocardial ischemia, and therefore deserve to be properly treated. The present article has the purpose to provide the readers with an overview about the role of FFR in the diagnosis and management of coronary artery disease, as well as the potential related controversies. The coronary physiology on the basis of this tool is also provided together with all the procedural aspects useful in the catheterization laboratory. In addition, the landmark trials on the basis of the FFR application in different clinical settings and coronary anatomies will be described, together with the main improvements aiming at favoring a more extensive use of this invasive tool.

Continuous intracoronary versus standard intravenous infusion of adenosine for fractional flow reserve assessment: the HYPEREMIC trial.

AIMS: The aim of this study was to evaluate the accuracy of a continuous intracoronary (IC) adenosine infusion, administered through the novel HYPEREM™IC over-the-wire microcatheter, to measure fractional flow reserve (FFR). METHODS AND RESULTS: The HYPEREMIC trial was a randomised, non-inferiority, crossover study in which patients with intermediate coronary lesions were enrolled for sequential pressure wire studies. FFR was measured using intravenous (IV) (140-180 mcg/kg/min) versus continuous non-weight-adjusted IC (360 mcg/min) adenosine. Patients were randomised and blinded to the order in which they received the adenosine, separated by a washout period. The primary endpoint was the mean hyperaemic FFR. Forty-one patients were enrolled at three UK sites between June and November 2016. The mean (standard deviation) FFR was 0.82 (±0.09) after IC versus 0.84 (±0.09) after IV adenosine. The difference of -0.02 (95% confidence interval [CI]: -0.03 to -0.01) confirmed the non-inferiority (margin <0.05) of IC to IV adenosine. Intracoronary adenosine was associated with a shorter mean time to maximal hyperaemia (difference -44 [95% CI: -59 to -29] seconds; p<0.0001). Chest discomfort was reported in 32/41 (78.0%) patients during IV adenosine versus 12/41 (29.3%) patients during IC adenosine. CONCLUSIONS: Continuous IC adenosine was a reliable, faster and better tolerated method of achieving maximal hyperaemia compared to IV adenosine.

Noninvasive assessment of increases in microvascular endothelial function following repeated bouts of hyperaemia.

OBJECTIVE: Spectral analyses of laser-Doppler signal can delineate underlying mechanisms in response to pharmacological agents and in cross-sectional studies of healthy and clinical populations. We tested whether spectral analyses can detect acute changes in endothelial function in response to a 6-week intervention of repeated bouts of hyperaemia. METHODS: Eleven males performed forearm occlusion (5 s with 10 s rest) for 30 min, 5 times/week for 6 weeks on one arm; the other was an untreated control. Skin blood flow was measured using laser-Doppler fluxmetry (LDF), and endothelial function was assessed with and without nitric oxide (NO) synthase-inhibition with L-NAME in response to local heating (42 °C and 44 °C) and acetylcholine. A wavelet transform was used for spectral analysis of frequency intervals associated with physiological functions. RESULTS: Basal measures were all unaffected by the hyperaemia intervention (all P > 0.05). In response to local skin heating to 42 °C, the 6 weeks hyperaemia intervention increased LDF, endothelial NO-independent and NO-dependent activity (all P ≤ 0.038). In response to peak local heating (44 °C) endothelial NO-independent and NO-dependent activity increased (both P ≤ 0.01); however, LDF did not (P > 0.2). In response to acetylcholine, LDF, endothelial NO-independent and NO-dependent activity all increased (all P ≤ 0.003) post-intervention. CONCLUSIONS: Spectral analysis appears sufficiently sensitive to measure changes over time in cutaneous endothelial activity that are consistent with standard physiological (local heating) and pharmacological (acetylcholine) interventions of assessing cutaneous endothelial function, and may be useful not only in research but also clinical diagnosis and treatment.

Impact of sublingual nitroglycerin dosage on FFRCT assessment and coronary luminal volume-to-myocardial mass ratio.

OBJECTIVES: Fractional flow reserve computed tomography (FFRCT) depends upon nitroglycerin (NTG) inducing maximal hyperemia. However, the impact of NTG dosages on FFRCT analysis including coronary volume-to-mass ratio (V/M) is unknown. METHODS: Eighty patients with repeat coronary CT angiograms (CCTAs) with different sublingual spray NTG doses (0.4 mg and 0.8 mg) were retrospectively analyzed with 45 patients excluded. Patient and scan demographics, post-stenosis and nadir FFRCT values, coronary volume, and coronary volume-to-mass ratio (V/M) were compared at initial CCTA (0.4 mg NTG) and follow-up CCTA (0.8 mg NTG). Differences were compared by Wilcoxon signed-rank test. RESULTS: Thirty-five patients were included (time between CCTAs, 3.9 ± 1.6 years). Segment involvement score was 2.4 ± 3.3 and 2.8 ± 3.4 at initial and repeat CCTA (0.4 and 0.8 mg NTG), respectively (p = 0.004). There was similar image quality (4.1 ± 0.7 vs 4.1 ± 0.8; p = 0.51). Nadir FFRCT values did not differ in the left (0.4 mg, 0.80 ± 0.08 vs 0.8 mg, 0.80 ± 0.03; p = 0.66), right (0.4 mg, 0.90 ± 0.04 vs 0.8 mg, 0.90 ± 0.06; p = 0.25), or circumflex coronaries (0.4 mg, 0.87 ± 0.06 vs 0.8 mg, 0.88 ± 0.06; p = 0.34). Post-stenosis FFRCT values did not differ (p = 0.65). Coronary volume increased with 0.8 mg of NTG (2639 ± 753 mm3 vs 2844.8 ± 827 mm3; p = 0.009) but V/M ratio did not (p = 0.20). CONCLUSIONS: Use of 0.8 mg versus 0.4 mg of NTG in routine clinical CCTAs significantly increased coronary volume determined from FFRCT analysis but did not alter FFRCT or V/M. Further evaluation of repeat CCTAs in a more contemporaneous fashion using varied nitrate doses and disease severity is needed. KEY POINTS: • Fractional flow reserve from computed tomography (FFRCT) is a noninvasive method for evaluating the coronary arteries and relies on nitroglycerin (NTG) to induce coronary vasodilation, but the impact of different NTG dosages is unknown. • Retrospective analysis evaluated use of different NTG doses on FFRCT. • Increased NTG dose increased coronary luminal volume on FFRCTanalysis, but did not change FFRCTvalues.

Assessment of endothelium-independent vasodilation: from methodology to clinical perspectives.

: Vascular response to exogenously administered nitroglycerine, an index of endothelium-independent vasodilation, has been used as a control test for the assessment of endothelium-dependent vasodilation (endothelial function) in humans. However, evidence has been accumulating that not only endothelium-dependent vasodilation but also endothelium-independent vasodilation per se is impaired in individuals with cardiovascular risk factors and cardiovascular disease. Impaired endothelium-independent vasodilation is associated with structural vascular alterations and alterations in vascular smooth muscle cells. Several methods, including assessment of vascular responses to vasoactive agents using angiography in a coronary artery and vascular responses to vasoactive agents using venous occlusion plethysmography and ultrasonography in a peripheral artery, are used to assess endothelium-independent vasodilation in humans. Measurement of endothelium-independent vasodilation is also useful for assessment of atherosclerosis and may be a predictor of future cardiovascular events. In this review, we focus on assessment of endothelium-independent vasodilation from methodology aspects to clinical perspectives.

Pharmacological assessment of the contribution of the arterial baroreflex to sympathetic discharge patterns in healthy humans.

To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside (NTP) and phenylephrine (PE) and measured action potential (AP) patterns with wavelet-based methodology. We hypothesized that 1) baroreflex unloading (NTP) would increase firing of low-threshold axons and recruitment of latent axons and 2) baroreflex loading (PE) would decrease firing of low-threshold axons. Heart rate (HR, ECG), arterial blood pressure (BP, brachial catheter), and muscle sympathetic nerve activity (MSNA, microneurography of peroneal nerve) were measured at baseline and during steady-state systemic, intravenous NTP (0.5-1.2 µg·kg-1·min-1, n = 13) or PE (0.2-1.0 µg·kg-1·min-1, n = 9) infusion. BP decreased and HR and integrated MSNA increased with NTP ( P < 0.01). AP incidence (326 ± 66 to 579 ± 129 APs/100 heartbeats) and AP content per integrated burst (8 ± 1 to 11 ± 2 APs/burst) increased with NTP ( P < 0.05). The firing probability of low-threshold axons increased with NTP, and recruitment of high-threshold axons was observed (22 ± 3 to 24 ± 3 max cluster number, 9 ± 1 to 11 ± 1 clusters/burst; P < 0.05). BP increased and HR and integrated MSNA decreased with PE ( P < 0.05). PE decreased AP incidence (406 ± 128 to 166 ± 42 APs/100 heartbeats) and resulted in fewer unique clusters (15 ± 2 to 9 ± 1 max cluster number, P < 0.05); components of an integrated burst (APs or clusters per burst) were not altered ( P > 0.05). These data support a hierarchical pattern of sympathetic neural activation during manipulation of baroreceptor afferent activity, with rate coding of active neurons playing the predominant role and recruitment/derecruitment of higher-threshold units occurring with steady-state hypotensive stress. NEW & NOTEWORTHY To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside and phenylephrine and measured sympathetic outflow with wavelet-based methodology. Baroreflex unloading increased sympathetic activity by increasing firing probability of low-threshold axons (rate coding) and recruiting new populations of high-threshold axons. Baroreflex loading decreased sympathetic activity by decreasing the firing probability of larger axons (derecruitment); however, the components of an integrated burst were unaffected.

Exercise versus vasodilator stress limb perfusion imaging for the assessment of peripheral artery disease.

PURPOSE: Our aim was to determine whether pharmacologic vasodilation is an alternative to exercise stress during limb perfusion imaging for peripheral artery disease (PAD). METHODS: Quantitative contrast-enhanced ultrasound (CEU) perfusion imaging of the bilateral anterior thigh and calf was performed in nine control subjects and nine patients with moderate to severe PAD at rest and during vasodilator stress with dipyridamole. For those who were able, CEU of the calf was then performed during modest plantar flexion exercise (20 watts). CEU time-intensity data were analyzed to quantify microvascular blood flow (MBF) and its parametric components of microvascular blood volume and flux rate. RESULTS: Thigh and calf skeletal muscle MBF at rest was similar between control and PAD patients. During dipyridamole, MBF increased minimally (

Pediatric pulmonary arterial hypertension: on the eve of growing up.

PURPOSE OF REVIEW: Current recommendations for diagnosis and treatment of pulmonary arterial hypertension (PAH) during childhood are expert opinion based, because of lacking pediatric data. In recent years, however, important pediatric data have emerged on PAH. RECENT FINDINGS: PAH in children shows similarities as well as differences compared to adults. Neonates and children know specific clinical presentations and a hemodynamic profile that differs from adults with PAH. Children identified as acute vasodilator responders according to the criteria proposed for adults rather than the pediatric criteria have better outcome when treated with calcium channel blockers. For nonresponders, combination PAH-targeted therapy leads to improved outcome compared to monotherapy. In pediatric PAH, WHO functional class, N-terminal pro-brain natriuretic peptide and tricuspid annular plane systolic excursion were identified as surrogates for survival and therefore qualify to be treatment goals in a goal-oriented treatment strategy. SUMMARY: In order to refine current pediatric treatment guidelines, data on efficacy of specific treatment regiments and strategies are needed. The recently validated composite endpoint of clinical worsening allows for trials that will provide these data. For the first time, evidence-based treatment goals have been identified that will allow for a goal-oriented treatment strategy. Furthermore, various prognostic predictors have been identified that may prove treatment goals in future.

Assessment of microvascular endothelial function in type 1 diabetes using laser speckle contrast imaging.

OBJECTIVE: To test whether laser speckle contrast imaging (LSCI) coupled with physiological post-occlusive reactive hyperemia (PORH) and pharmacological iontophoresis of acetylcholine (ACh) as local vasodilator stimuli could distinguish between cutaneous microvascular responses of Type 1 Diabetes (T1DM)'s patients with endothelial dysfunction and that of healthy controls. METHODS: Patients with T1DM aged ≥12years completed a clinical-epidemiological questionnaire. Data detailing patients' such as daily insulin dose, duration of diabetes, and use of pharmaceuticals such as antihypertensive drugs and statins that could interfere with endothelial function were obtained. Vascular reactivity was assessed in the forearm by LSCI and PORH at baseline and during iontophoresis of ACh using increasing anodic currents of 30, 60, 90, 120, 150 and 180µA in 10second intervals. RESULTS: This study included 50 patients with T1DM and 30 control subjects. The mean resting flux did not differ between patients and control subjects. T1DM patients exhibited endothelial dysfunction upon challenge with physiological or pharmacological stimuli. The microvascular response to both ACh and PORH (i.e., maximum response at peak and amplitude) were significantly reduced in patients with diabetes compared with control subjects (p<0.001). CONCLUSION: We demonstrated that endothelium-dependent skin microvascular vasodilator responses are significantly impaired in patients with T1DM compared to healthy subjects investigated using LSCI coupled with ACh iontophoresis and PORH. Additionally, we find that LSCI is a promising methodology for studying physiological vascular reactivity in T1DM.

An assessment of the safety, hemodynamic response, and diagnostic accuracy of commonly used vasodilator stressors in patients with severe aortic stenosis.

BACKGROUND: Increasing numbers of patients are undergoing transcatheter aortic valve replacement, which often involves assessment of coronary artery disease ischemic burden. The safety and diagnostic accuracy of vasodilator stress agents in patients with severe aortic stenosis (AS) undergoing SPECT myocardial perfusion imaging (MPI) has not been established. METHODS: Patients with severe AS (valve area <1 cm2) on echocardiography who underwent vasodilator stress SPECT MPI at two centers were identified. Patients with aortic valve intervention prior to MPI or who underwent concurrent exercise during stress testing were excluded. AS patients were matched to controls without AS based on age, gender, BMI, ejection fraction, and stress agent. Symptoms, serious adverse events, hemodynamic response, and correlation to invasive angiography were assessed. RESULTS: A total of 95 cases were identified with 45% undergoing regadenoson, 31% dipyridamole, and 24% adenosine stress. A significant change in systolic blood pressure (BP), cases vs controls, was observed with adenosine [-17.9 ± 20.1 vs -2.6 ± 24.9 P = .03)], with a trend toward significance with regadenoson [-16.8 ± 20.3 vs -9.4 ± 17.9 (P = .08)] and dipyridamole [-17.8 ± 20.6 vs -9.0 ± 12.1 (P = .05)]. The change in heart rate was significantly different only for adenosine [5.3 ± 16.8 vs 14.2 ± 10.8 (P = .04)]. Overall, 45% of cases vs 24% of controls (P = .004) had a >20 mmHg decrease in systolic BP. Age, BMI, and resting systolic BP were related to a >20 mmHg decrease in systolic BP on univariate analysis, although only higher resting systolic BP was a predictor on multivariate analysis. In 33 patients who underwent angiography, the sensitivity, specificity, and diagnostic accuracy of vasodilator stress MPI was 77%, 69%, and 73%, respectively. No serious adverse events occurred in the severe AS patients. CONCLUSION: Severe AS patients are more likely to have a hemodynamically significant decrease in systolic BP with vasodilator stress. There were no serious adverse events in this severe AS cohort with good diagnostic performance of MPI compared to angiography.

The reproducibility and prognostic value of serial measurements of heart rate response to regadenoson during myocardial perfusion imaging.

PURPOSE: The heart rate response (HRR, percentage change from baseline) to regadenoson during myocardial perfusion imaging (MPI) can provide incremental prognostic value in patients with known or suspected coronary artery disease. Our purpose was to evaluate the variability and prognostic value of HRR on serial measurements. METHODS: We studied 648 consecutive patients (61 ± 11 years, 48 % with diabetes) who underwent two regadenoson MPI studies (16 ± 9 months between studies). HRR <30 % was defined as abnormal. All-cause mortality was determined by chart review and verified using the US Social Security Death Master File. RESULTS: HRR was well correlated between the two studies (intraclass correlation coefficient 0.72, 95 % CI 0.67 - 0.76) with no systematic bias (mean difference 0.88 %, p = 0.2) or proportional bias (p = 0.5) by Bland-Altman analysis in all patients and in those with normal MPI on both studies. Of the 308 patients (48 %) with normal baseline HRR (HRR-1), 33 % had developed a blunted HRR on the second MPI study (HRR-2). Older age, male gender, end-stage renal disease, and abnormal baseline left ventricular ejection fraction were independent predictors of a new-onset abnormal HRR. During a mean follow-up of 2.4 ± 1.2 years, 55 patients (8.5 %) died. Patients with a blunted HRR-1 had increased mortality risk irrespective of their HRR-2 (p = 0.9, log-rank test). Among patients with normal HRR-1, a blunted HRR-2 was an independent predictor of all-cause mortality beyond clinical and traditional MPI data (hazard ratio 2.83, 95 % CI 1.14 - 7.03). Finally, patients with a normal HRR-1 and HRR-2 had the lowest event rate, while those with any abnormal HRR had an increased risk of death (hazard ratio 2.5, 95 % CI 1.2 - 5.4). CONCLUSION: There was good correlation in the HRR to regadenoson on serial measurements without systematic or proportional biases. Patients with consistently normal HRR had the best prognosis.

Assessment of penile erection methods in rhesus macaques to model pharmacokinetics of antiretroviral drugs and penile infection with simian immunodeficiency virus.

BACKGROUND: An established macaque model to assess HIV interventions against penile transmission is currently not available. Physiological changes during penile erections may affect susceptibility to infection and drug pharmacokinetics (PK). Here, we identify methods to establish erections in macaques to evaluate penile transmission, PK, and efficacy under physiologic conditions. METHODS: Penile rigidity and length were evaluated in eight rhesus macaques following rectal electrostimulation (RES), vibratory stimulation (VS), or pharmacological treatment with Sildenafil Citrate (Viagra) or Alprostadil. RESULTS: Rectal electrostimulation treatment increased penile rigidity (>82%) and length (2.5 ± 0.58 cm), albeit the response was transient. In contrast, VS alone or coupled with Viagra or Alprostadil failed to elicit an erection response. CONCLUSION: Rectal electrostimulation treatment elicits transient but consistent penile erections in macaques. High rigidity following RES treatment demonstrates increased blood flow and may provide a functional model for penile PK evaluations and possibly simian immunodeficiency virus (SIV) transmission under erect conditions.

Real-Time, In Vivo Monitoring, and Quantitative Assessment of Intra-Arterial Vasospasm Therapy.

BACKGROUND: Our study aimed to evaluate whether the effect of an intra-arterial vasospasm therapy can be assessed quantitatively by in vivo blood flow analysis using the postprocessing algorithm parametric color coding (PCC). METHODS: We evaluated 17 patients presenting with acute clinical deterioration due to vasospasm following subarachnoidal hemorrhage treated with intra-arterial nimodipine application. Pre- and post-interventional DSA series were post-processed by PCC. The relative time to maximum opacification (rTmax) was calculated in 14 arterially and venously located points of interest. From that data, the pre- and post-interventional cerebral circulation time (CirT) was calculated. Additionally, the arterial vessel diameters were measured. Pre- and post-interventional values were compared and tested for significance, respectively. RESULTS: Flow analysis revealed in all arterial vessel segments a non-statistically significant prolongation of rTmax after treatment. The mean CirT was 5.62 s (±1.19 s) pre-interventionally and 5.16 s (±0.81 s) post-interventionally, and the difference turned out as statistically significant (p = 0.039). A significantly increased diameter was measurable in all arterial segments post-interventionally. CONCLUSION: PCC is a fast applicable imaging technique that allows via real-time and in vivo blood flow analysis a quantitative assessment of the effect of intra-arterial vasospasm therapy. Our results seem to validate in vivo that an intra-arterial nimodipine application induces not only vasodilatation of the larger vessels, but also improves the microcirculatory flow, leading to a shortened cerebral CirT that reaches normal range post-interventionally. Procedural monitoring via PCC offers the option to compare quantitatively different therapy regimes, which allows optimization of existing approaches and implementation of individualized treatment strategies.