Mapping Microvascular Flow via Radon Transform Ultrasound: Technical Advances and Pilot Application

Higher Myocardial and Skeletal Muscle Microvascular Flow in Sickle Cell Disease Patients on Hydroxyurea

Quantitative measurement of post-reperfusion epicardial flow velocity by a Doppler guidewire can predict clinical cardiac events in patients with acute myocardial infarction (AMI). It has also been reported that the coronary flow velocity pattern in patients with microvascular dysfunction is characterized by the presence of early systolic retrograde flow and a rapid diastolic deceleration time (DDT). The purpose of this study was to examine the role of assessing both epicardial flow velocity and microvascular damage in the prediction of in-hospital complications and survival after percutaneous coronary intervention (PCI). Two hundred and eleven consecutive patients with first anterior AMI who underwent successful PCI were subjected to coronary flow measurement immediately after successful PCI with a Doppler guidewire. The coronary flow velocity spectrum provided the following parameters: time-averaged peak velocity (cm/s, APV), systolic peak velocity (cm/s) and DDT (ms). We defined the presence of microvascular dysfunction as DDT ≤600 ms and the presence of systolic flow reversal, and slow epicardial flow as resting APV ≤10cm/s. We classified the patients into three categories: without microvascular dysfunction (group 1, n=122), with microvascular dysfunction and normal epicardial flow (group 2, n= 54), with microvascular dysfunction and slow epicardial flow (group 3, n=35). The clinical event rate was compared among the 3 groups. The in-hospital event rates for congestive heart failure, cardiac rupture and death were highest in group 3 and lowest in group 1 (Table ). Assessment of both coronary microvascular damage and epicardial flow velocity can accurately predict in-hospital complications and survival in AMI patients who underwent successful reperfusion of the infarct-related coronary artery, identifying a subset of high risk patients. In-hospital event rates (%)

Dysfunction of the transition from fetal to neonatal circulatory systems may be a major contributor to poor outcome following preterm birth. Evidence exists in the human for both a period of low flow between 5 and 11 h and a later period of increased flow, suggesting a hypoperfusion–reperfusion cycle over the first 24 h following birth. Little is known about the regulation of peripheral blood flow during this time. The aim of this study was to conduct a comparative study between the human and guinea pig to characterize peripheral microvascular behavior during circulatory transition. Very preterm (≤28 weeks GA), preterm (29–36 weeks GA), and term (≥37 weeks GA) human neonates underwent laser Doppler analysis of skin microvascular blood flow at 6 and 24 h from birth. Guinea pig neonates were delivered prematurely (62 day GA) or at term (68–71 day GA) and laser Doppler analysis of skin microvascular blood flow was assessed every 2 h from birth. In human preterm neonates, there is a period of high microvascular flow at 24 h after birth. No period of low flow was observed at 6 h. In preterm animals, microvascular flow increased after birth, reaching a peak at 10 h postnatal age. Blood flow then steadily decreased, returning to delivery levels by 24 h. Preterm birth was associated with higher baseline microvascular flow throughout the study period in both human and guinea pig neonates. The findings do not support a hypoperfusion–reperfusion cycle in the microcirculation during circulatory transition. The guinea pig model of preterm birth will allow further investigation of the mechanisms underlying microvascular function and dysfunction during the initial extrauterine period.

We examined leg glucose uptake (GU), net phenylalanine uptake (PheU) and Phe net balance (PheNB) in sixteen older (O) and seventeen younger (Y) adults who received either a vasodilator (sodium nitroprusside, SNP: N=8 O and N=8 Y) or performed aerobic exercise (EX: N=8 O and N=9 Y) to induce similar increases in microvascular blood flow and capillary recruitment. We hypothesized that muscle contraction and exercise per se, in the presence of amino acids, would result in greater increases in skeletal muscle substrate utilization than peripheral vasodilation (SNP) without contraction. Indocyanine green (ICG) was used to measure limb blood flow (LBF) and contrast‐enhanced ultrasound to measure microvascular blood volume (MBV, an indicator of capillary recruitment), microvascular flow velocity (MFV) and microvascular blood flow (MBV x MFV). GU, PheU, PheNB and all blood flow measures were obtained 60 min after SNP or EX. LBF, MBV, MFV, microvascular blood flow, GU, PheU, and PheNB were all similarly increased in response to SNP and EX in both age groups. Thus, vasodilation in the absence of muscle contraction is capable of increasing skeletal muscle substrate utilization to a similar extent as aerobic exercise; likely by increasing microvascular blood flow and capillary recruitment. These results indicate that common vasodilators, not unlike exercise, may promote favorable metabolic responses in skeletal muscle.

Introduction: Current treatments for ischemia after stroke have not focused directly on the physiological effects of restoring or improving cerebral microvascular perfusion. Nanomolar concentrations of drag-reducing polymers (DRP) have been shown to improve hemodynamics and survival in animal models of the ischemic myocardium and peripheral circulation. We recently demonstrated that DRP improved microvascular perfusion in normal and traumatized rat brain. We hypothesized that DRP restores microvascular perfusion after focal ischemia and improves neurologic recovery in the rat. Methods: The suture permanent middle cerebral artery occlusion (MCAO) model in the rat was used. DRP was injected i.v. 90 minutes after MCAO. Controls were injected with an equal volume of saline. Using in vivo 2-photon laser scanning microscopy over the parietal cortex, we studied the acute effects of DRP on microvascular blood flow velocity, tissue oxygenation (NADH) and blood brain barrier (BBB) permeability for 5 hr after MCAO. Doppler cortical flow, rectal and cranial temperatures, arterial pressure, blood gases and electrolytes were monitored. Cerebral infarction was evaluated by triphenyltetrazolium chloride (TTC) staining 24 hr after MCAO and motor function by Rotarod at one week. Results: MCAO resulted in a progressive decrease in microvascular flow in the penumbra of the parietal cortex with hypoxia and increased BBB permeability during 5 hr monitored. DRP partially restored microvascular flow compared to control (21±6.7%, Mean ± SEM, p<0.05, n=4) and reduced the progression of ischemia and BBB permeability by 14±4.6 and 18±6.5%, respectively (p<0.05). Infarction volume was reduced by 24±8.1% in DRP treated rats (n=2, p<0.05). The Rotarod tests showed that one week after MCAO, DRP treated rats performed better than saline treated rats with times of 75.6±16.0% and 47.3±16.0%, respectively, as percent of normal rats. Conclusions: DRP restores cerebral microvascular flow after MCAO reducing tissue hypoxia and BBB damage. The improvement in flow is reflected by a reduction in infarct size 24 hours after MCAO and by improved motor neurological recovery at one week after MCAO. DRP can be a new effective therapy for ischemic stroke targeting microvascular perfusion.

Obesity is associated with resistance to the metabolic (glucose uptake) and vascular (nitric-oxide mediated dilation and microvascular recruitment) actions of insulin. These vascular effects contribute to insulin sensitivity by increasing tissue delivery of glucose. Studies by us and others suggest that sympathetic activation contributes to insulin resistance to glucose uptake. Here we tested the hypothesis that sympathetic activation contributes to impaired insulin-mediated vasodilation in adult subjects with obesity. In a randomized crossover study, we used a euglycemic hyperinsulinemic clamp in 12 subjects with obesity to induce forearm arterial vasodilation (forearm blood flow) and microvascular recruitment (contrast-enhanced ultrasonography) during an intrabrachial infusion of saline (control) or phentolamine (sympathetic blockade). Insulin increased forearm blood flow on both study days (from 2.21±1.22 to 4.89±4.21 mL/100 mL per min, P=0.003 and from 2.42±0.89 to 7.19±3.35 mL/100 mL per min, P=0.002 for the intact and blocked day, respectively). Sympathetic blockade with phentolamine resulted in a significantly greater increase in microvascular flow velocity (∆microvascular flow velocity: 0.23±0.65 versus 2.51±3.01 arbitrary intensity units (AIU/s) for saline and phentolamine respectively, P=0.005), microvascular blood volume (∆microvascular blood volume: 1.69±2.45 versus 3.76±2.93 AIU, respectively, P=0.05), and microvascular blood flow (∆microvascular blood flow: 0.28±0.653 versus 2.51±3.01 AIU2/s, respectively, P=0.0161). To evaluate if this effect was not due to nonspecific vasodilation, we replicated the study in 6 subjects with obesity comparing intrabrachial infusion of phentolamine to sodium nitroprusside. At doses that produced similar increases in forearm blood flow, insulin-induced changes in microvascular flow velocity were greater during phentolamine than sodium nitroprusside (%microvascular flow velocity=58% versus 29%, respectively, P=0.031). We conclude that sympathetic activation impairs insulin-mediated microvascular recruitment in adult subjects with obesity.

Microvascular and macrovascular flow are uncoupled in early polymicrobial sepsis

Effect of vasodilator hydralazine on tumor microvascular random flow and blood volume as measured by intravoxel incoherent motion (IVIM) weighted MRI in conjunction with Gd-DTPA-Albumin enhanced MRI

Purpose: Leg muscle microvascular blood flow (perfusion) is impaired in response to maximal exercise in patients with peripheral artery disease (PAD); however, during submaximal exercise, microvascular perfusion is maintained due to a greater increase in microvascular blood volume compared with that seen in healthy adults. It is unclear whether this submaximal exercise response reflects a microvascular impairment, or whether it is a compensatory response for the limited conduit artery flow in PAD. Therefore, to clarify the role of conduit artery blood flow, we compared whole-limb blood flow and skeletal muscle microvascular perfusion responses with exercise in patients with PAD (n=9; 60±7 years) prior to, and following, lower-limb endovascular revascularization. Materials and Methods: Microvascular perfusion (microvascular volume × flow velocity) of the medial gastrocnemius muscle was measured before and immediately after a 5 minute bout of submaximal intermittent isometric plantar-flexion exercise using contrast-enhanced ultrasound imaging. Exercise contraction-by-contraction whole-leg blood flow and vascular conductance were measured using strain-gauge plethysmography. Results: With revascularization there was a significant increase in whole-leg blood flow and conductance during exercise (p<0.05). Exercise-induced muscle microvascular perfusion response did not change with revascularization (pre-revascularization: 3.19±2.32; post-revascularization: 3.89±1.67 aU.s−1; p=0.38). However, the parameters that determine microvascular perfusion changed, with a reduction in the microvascular volume response to exercise (pre-revascularization: 6.76±3.56; post-revascularization: 2.42±0.69 aU; p<0.01) and an increase in microvascular flow velocity (pre-revascularization: 0.25±0.13; post-revascularization: 0.59±0.25 s−1; p=0.02). Conclusion: These findings suggest that patients with PAD compensate for the conduit artery blood flow impairment with an increase in microvascular blood volume to maintain muscle perfusion during submaximal exercise. Clinical Impact The findings from this study support the notion that the impairment in conduit artery blood flow in patients with PAD leads to compensatory changes in microvascular blood volume and flow velocity to maintain muscle microvascular perfusion during submaximal leg exercise. Moreover, this study demonstrates that these microvascular changes are reversed and become normalized with successful lower-limb endovascular revascularization.

BackgroundReduction in capillaries number is the defining feature of microvascular disease in Systemic Sclerosis (SSc) and it concurs to the ischemic manifestations of the disease. Digital Ulcers (DUs) are the...

BackgroundTo explore the protective effects of Shexiang Tongxin Dropping Pill (STP) in improving peripheral microvascular dysfunction in mice and to explore the involved mechanism.Material/MethodsA peripheral microvascular dysfunction model was established by combined myocardial infarction (MI) and lipopolysaccharide (LPS) injection in mice. Then, the mice were randomized into a model group (n=10) or an STP group (n=10), which were treated with normal saline and STP, respectively. The cremaster muscle microvascular blood flow velocity and numbers of leukocytes adherent to the venular wall were evaluated before and after drug intervention. We assessed the expression of adhesion molecule CD11b and related transcript factor FOXO1 in leukocytes, cystathionine-γ-lyase (CSE) mRNA expression in the cremaster muscle, and mitochondrial DNA copy numbers.ResultsCompared with those of control mice, the cremaster microvascular blood flow velocity, cremaster CSE expression, and mitochondrial DNA copy number in mice from the model group were significantly lower and leukocyte adhesion and CD11b and FOXO1 expression were significantly higher. Intervention with STP could significantly increase the cremaster microvascular flow velocity (0.480±0.010 mm/s vs. 0.075±0.005 mm/s), mRNA expression of cremaster CSE, and mitochondrial DNA copy number, but it inhibited leukocyte adhesion and decreased leukocyte CD11b and FOXO1 expression.ConclusionsSTP significantly improved peripheral microcirculation, in which increased CSE expression might be the underlying mechanism.

Assessment of coronary microcirculation alterations in a porcine model of no-reflow using ultrasound localization microscopy: a proof of concept study.

Mortality in acute kidney injury (AKI) patients remains very high, although very important advances in understanding the pathophysiology and in diagnosis and supportive care have been made. Most commonly, adverse outcomes are related to extra-renal organ dysfunction and failure. We and others have documented inflammation in remote organs as well as microvascular dysfunction in the kidney after renal ischemia. We hypothesized that abnormal microvascular flow in AKI extends to distant organs. To test this hypothesis, we employed intravital multiphoton fluorescence imaging in a well-characterized rat model of renal ischemia/reperfusion. Marked abnormalities in microvascular flow were seen in every organ evaluated, with decreases up to 46% observed 48 hours postischemia (as compared to sham surgery, p = 0.002). Decreased microvascular plasma flow was found in areas of erythrocyte aggregation and leukocyte adherence to endothelia. Intravital microscopy allowed the characterization of the erythrocyte formations as rouleaux that flowed as one-dimensional aggregates. Observed microvascular abnormalities were associated with significantly elevated fibrinogen levels. Plasma flow within capillaries as well as microthrombi, but not adherent leukocytes, were significantly improved by treatment with the platelet aggregation inhibitor dipyridamole. These microvascular defects may, in part, explain known distant organ dysfunction associated with renal ischemia. The results of these studies are relevant to human acute kidney injury.

Angiotensin-(1-7) [Ang-(1-7)], an endogenous ligand for the G protein-coupled receptor Mas, exerts both vasodilatory and insulin-sensitizing effects. In skeletal muscle, relaxation of precapillary arterioles recruits microvasculature and increases the endothelial surface area available for nutrient and hormone exchanges. To assess whether Ang-(1-7) recruits microvasculature and enhances insulin action in muscle, overnight-fasted adult rats received an intravenous infusion of Ang-(1-7) (0, 10, or 100 ng/kg per minute) for 150 minutes with or without a simultaneous infusion of the Mas inhibitor A-779 and a superimposition of a euglycemic insulin clamp (3 mU/kg per minute) from 30 to 150 minutes. Hind limb muscle microvascular blood volume, microvascular flow velocity, and microvascular blood flow were determined. Myographic changes in tension were measured on preconstricted distal saphenous artery. Ang-(1-7) dose-dependently relaxed the saphenous artery (P<0.05) ex vivo. This effect was potentiated by insulin (P<0.01) and abolished by either endothelium denudement or Mas inhibition. Systemic infusion of Ang-(1-7) rapidly increased muscle microvascular blood volume and microvascular blood flow (P<0.05, each) without altering microvascular flow velocity. Insulin infusion alone increased muscle microvascular blood volume by 60% to 70% (P<0.05). Adding insulin to the Ang-(1-7) infusion further increased muscle microvascular blood volume and microvascular blood flow (≈2.5 fold; P<0.01). These were associated with a significant increase in insulin-mediated glucose disposal and muscle protein kinase B and extracellular signal-regulated kinase 1/2 phosphorylation. A-779 pretreatment blunted the microvascular and insulin-sensitizing effects of Ang-(1-7). We conclude that Ang-(1-7) by activating Mas recruits muscle microvasculature and enhances the metabolic action of insulin. These effects may contribute to the cardiovascular protective responses associated with Mas activation and explain the insulin-sensitizing action of Ang-(1-7).

Department of Neurology; University of Miami Miller School of Medicine; Miami, FL The author received grant support from the National Institutes of Health.