Abnormalities In Microvascular Function Research Articles

Association between coronary microvascular function and the vasa vasorum in patients with early coronary artery disease

Background and aimsThe vasa vasorum (VV) plays a role in the initial phase of atherosclerosis, and abnormalities in microvascular function may be sensitive measures of the early development of atherosclerosis. The current study was designed to access the association between coronary microvascular function and VV density in patients undergoing cardiac catheterization. MethodsTwenty-four patients with early coronary artery disease underwent endothelium-dependent (coronary blood flow, CBF) and endothelium-independent (coronary flow velocity reserve, CFVR) coronary microvascular function testing, and optical coherence tomography (OCT) imaging of the left anterior descending coronary artery (LAD). Using an intracoronary Doppler guidewire, CBF was examined by evaluating changes in blood flow in response to acetylcholine and CFVR in response to adenosine. VV density (VV volume/vessel volume × 100, %VV) of the proximal 10 mm of the LAD was quantified by OCT. ResultsThe median values (Q1, Q3) of CFVR, % changes in CBF in response to acetylcholine, and the %VV were 2.70 (2.30, 2.90), −16.82 (−42.34, 54.52), and 2.62 (2.35, 3.35), respectively. %VV correlated inversely with CBF (r = −0.614, p = 0.001) and directly with CFVR (r = 0.423, p = 0.040). Multivariate analysis showed that only %VV was significantly correlated with CBF and the association was independent of other clinical variables, Framingham risk score, body mass index, and a family history of coronary heart disease. ConclusionsThis study demonstrates that VV density has negative correlation with endothelium-dependent microvascular function in patients with early coronary atherosclerosis. These observations link adventitial VV structure and function to microvascular dysfunction in early coronary atherosclerosis.

Effect of diabetes on the cutaneous microcirculation of the feet in patients with intermittent claudication.

To evaluate endothelial-dependent and - independent cutaneous vasodilator responses in the feet of patients with peripheral arterial disease (PAD) with or without Type 2 diabetes. Cutaneous microvascular responses in the dorsum of both lower limbs were measured in the supine position using Laser Doppler Fluximetry combined with iontophoretic administration of endothelial-dependent (acetylcholine, Ach) and -independent (sodium nitroprusside, SNP) vasodilators in diabetic (n = 19) and non diabetic (n = 17) patients with PAD (presenting as unilateral calf intermittent claudication (IC). In patients with diabetes and IC, endothelial-dependent vasodilation was significantly impaired in the symptomatic limb [74 (57,105) vs 68 (24,81) PU, Z =-2.79, p = 0.005] compared to the asymptomatic limb. Patients without diabetes showed no impairment of vasodilation. Resting ankle-brachial pressure index did not identify the presence of abnormalities in microvascular function. The combination of diabetes and PAD is associated with a reduction in endothelial-dependent cutaneous vasodilation in the feet without an associated reduction in endothelial independent vasodilation.

Abnormal myocardial perfusion correlates with impaired systolic strain and diastolic strain rate in systemic lupus erythematosus: a cardiovascular magnetic resonance study

index (MPRI) was lower in SLE compared to controls (1.4 ± 0.2 vs. 1.9 ± 0.4, p<0.001), shown in Table 2. A third of lupus patients had visual evidence of non-segmental subendocardial perfusion defects, in keeping with microvascular dysfunction. No segmental perfusion defects were observed to suggest presence of epicardial coronary artery disease. There was no significant difference in LV size, mass and ejection fraction between SLE patients and controls. Peak systolic circumferential strain (-17.2 ± 1.7 vs. -19.4 ± 1.2, p<0.001) and peak diastolic strain rate (78 ± 24 vs. 118 ± 15 s -1 , p<0.001) were impaired in SLE patients. In SLE, MPRI showed a significant correlation with peak systolic strain (R= -0.76, p<0.001) and peak diastolic strain rate (R= 0.65, p<0.001), depicted in Figure 1. Conclusions Myocardial perfusion is impaired in patients with SLE with no known heart disease. In these patients, impaired MPRI was associated with abnormal myocardial deformation characteristics. It is likely that chronic disease activity and myocardial inflammation results in abnormalities in microvascular function which predate the development of myocardial functional derangements. CMR is an important tool for assessment of subclinical myocardial disease in SLE. Funding

Wavelet Analysis of Doppler Flow Velocity Waveforms from the Ocular Circulation Detects Abnormalities in Micro-vascular Function in Heart Failure

Aims: Many pathological processes may result in Heart Failure (HF), however, the final clinical phenotype appears to be common to all aetiologies. Microvascular abnormalities in HF have been demonstrated in a variety of vascular beds however the effect of HF on the retrobulbar circulation is not known. We employed a novel method of analysing blood flow velocity waveforms in order to quantify changes in the Doppler signal obtained from the retrobulbar arteries between HF patients and controls. FMD was also assessed. Methods and Results: 32 patients with systolic HF on maximal medical therapy and 10 age and sex-matched controls were studied. Doppler waveforms were obtained from the ophthalmic, central retinal and brachial artery in all subjects. Waveforms were analysed using a wavelet technique which expressed each waveform in constituent frequency bands, allowing direct comparisons to be made. Significant differences were found in ophthalmic and central retinal waveforms but not brachial waveforms between patients and controls. Flow mediated dilatation was also found to be abnormal in patients. Conclusion: This study suggests that abnormalities in microvascular function in the retrobulbar circulation are present in HF and that these changes can be detected by a novel wavelet analysis technique.

Analysis of slow wave oscillations in cerebral haemodynamics and metabolism following subarachnoid haemorrhage.

Aneurysmal subarachnoid haemorrhage (SAH) causes the greatest loss of productive life years of any form of stroke. Emerging concepts of pathophysiology highlight early abnormalities of microvascular function, including impaired autoregulation of cerebral blood flow and flow-metabolism coupling, as key causes of cerebral ischaemia and poor outcome. Near infrared spectroscopy (NIRS) is a non-invasive optical technique which may help identify cerebral microvascular dysfunction. The aim of this research is to investigate the status of flow-metabolism coupling by examining phase relationships between NIRS-derived concentrations of oxy-haemoglobin ([HbO2]), deoxy-haemoglobin ([HHb]) and cytochrome c oxidase oxidation ([oxCCO]). Eight sedated ventilated patients with SAH were investigated. A combined NIRS broadband and frequency domain spectroscopy system was used to measure [HbO2], [HHb] and [oxCCO] alongside other multimodal neuromonitoring. Wavelet analysis of phase relationships revealed antiphase [HbO2]-[oxCCO] and in-phase [HbO2]-[HHb] oscillations between 0.1Hz-0.01Hz consistent with compromised flow-metabolism coupling. NIRS derived variables might offer unique insights into microvascular and metabolic dysfunction following SAH, and in the future identify therapeutic windows or targets.

Globotriaosylsphingosine Accumulation and Not Alpha-Galactosidase-A Deficiency Causes Endothelial Dysfunction in Fabry Disease

BackgroundFabry disease (FD) is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (GLA) resulting in the accumulation of globotriaosylsphingosine (Gb3) in a variety of tissues. While GLA deficiency was always considered as the fulcrum of the disease, recent attention shifted towards studying the mechanisms through which Gb3 accumulation in vascular cells leads to endothelial dysfunction and eventually multiorgan failure. In addition to the well-described macrovascular disease, FD is also characterized by abnormalities of microvascular function, which have been demonstrated by measurements of myocardial blood flow and coronary flow reserve. To date, the relative importance of Gb3 accumulation versus GLA deficiency in causing endothelial dysfunction is not fully understood; furthermore, its differential effects on cardiac micro- and macrovascular endothelial cells are not known.Methods and ResultsIn order to assess the effects of Gb3 accumulation versus GLA deficiency, human macro- and microvascular cardiac endothelial cells (ECs) were incubated with Gb3 or silenced by siRNA to GLA. Gb3 loading caused deregulation of several key endothelial pathways such as eNOS, iNOS, COX-1 and COX-2, while GLA silencing showed no effects. Cardiac microvascular ECs showed a greater susceptibility to Gb3 loading as compared to macrovascular ECs.ConclusionsDeregulation of key endothelial pathways as observed in FD vasculopathy is likely caused by intracellular Gb3 accumulation rather than deficiency of GLA. Human microvascular ECs, as opposed to macrovascular ECs, seem to be affected earlier and more severely by Gb3 accumulation and this notion may prove fundamental for future progresses in early diagnosis and management of FD patients.

Microvascular function is preserved in newly diagnosed rheumatoid arthritis and low systemic inflammatory activity

Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality. Microvascular function has been linked to several risk factors for cardiovascular disease and may be affected in RA. It is, however, presently unknown at what point in the disease course the abnormalities in microvascular function occur. We determined whether microvascular function is already disturbed in early disease-modifying antirheumatic drugs (DMARD)-naive RA patients with low systemic inflammation. Fifteen consecutive RA patients with a median symptom duration of 5 months, a C-reactive protein level of ≤20 mg/l and without a history of cardiovascular disease, and age 15 and sex-matched healthy controls were recruited. Endothelium-dependent and endothelium-independent vasodilatation in skin was evaluated with laser Doppler fluxmetry after iontophoresis of acetylcholine and sodium nitroprusside, respectively. Videomicroscopy was used to measure recruitment of skin capillaries after arterial occlusion. CRP and ESR levels were mildly, but significantly elevated in patients compared to controls. No differences in both endothelium-dependent vasodilatation and capillary recruitment were observed between groups [709% (95% CI, 457–961%) vs 797% (95% CI, 556–1,037%), P = 0.59 and 37% (95% CI, 26–47%) vs 41% (95% CI, 31–50%), P = 0.59, respectively]. Skin microvascular function is preserved in early, DMARD-naive RA patients with moderately active RA but low systemic inflammatory activity. Both the extent of the systemic inflammation and disease duration, therefore, may be important determinants of microvascular dysfunction and subsequent increased risk for cardiovascular disease.

Limb Stress-Rest Perfusion Imaging With Contrast Ultrasound for the Assessment of Peripheral Arterial Disease Severity

We hypothesized that stress-rest perfusion imaging of skeletal muscle in the lower extremity with contrast-enhanced ultrasound (CEU) could evaluate the severity of peripheral arterial disease (PAD). Perfusion imaging may provide valuable quantitative information on PAD, particularly in patients with diabetes in whom microvascular functional abnormalities are common. Study subjects included 26 control subjects and 39 patients with symptomatic PAD, 19 of whom had type 2 diabetes mellitus. A modified treadmill exercise test was performed to determine exercise time to development of claudication. Multilevel pulse-volume recordings and ankle-brachial index (ABI) at rest and post-exercise ABI were measured in both extremities. Microvascular blood flow in the gastrocnemius and soleus muscles was measured at rest and after 2 min of calibrated plantar-flexion exercise. During exercise, claudication did not occur in normal subjects and occurred earlier in PAD patients with diabetes than without (median time 1.2 min [95% confidence interval (CI) 0.6 to 2.5] vs. 3.0 min [95% CI 2.1 to 6.0], p < 0.01). Compared to control subjects, patients with PAD had lower skeletal muscle blood flow during plantar-flexion exercise and lower flow reserve on CEU. After adjusting for diabetes, the only diagnostic tests that predicted severity of disease by claudication threshold were CEU exercise blood flow and flow reserve (odds ratios 0.67 [95% CI 0.51 to 0.88; p = 0.003] and 0.64 [95% CI 0.46 to 0.89, p = 0.008], respectively). A quasi-likelihood information analysis incorporating all non-invasive diagnostic tests indicated that the best models for predicting severity of disease were the combination of diabetes and either exercise blood flow or flow-reserve on CEU. Perfusion imaging of limb skeletal during exercise and measurement of absolute flow reserve can provide valuable information on the severity PAD. This strategy may be useful for evaluating the total impact of disease in patients with complex disease or those with coexisting functional abnormalities of flow regulation.

Microvascular changes in the peripheral microcirculation of women with chronic pelvic pain due to congestion.

Pelvic venous congestion is a common finding in women with chronic pelvic pain. While the pathophysiology of this condition is poorly understood, there are clear indications that it involves vascular dysfunction. The present studies sought abnormalities in microvascular function in these patients. Prospective longitudinal study. A teaching hospital tertiary referral. Eighteen women with pelvic congestion and 13 normal women. Parameters of microcirculatory function were measured in the calves of women using venous congestion plethysmography during the midfollicular and midluteal phases of the menstrual cycle. The women with pelvic congestion were studied again after treatment for the condition. Isovolumetric venous pressure, microvascular filtration capacity and limb blood flow. Of the measured parameters of microvascular function, only isovolumetric venous pressure (Pvi) was significantly higher in women with congestion when compared to the controls during the same phase of the cycle. There were no menstrual cycle related differences in any of the other measured parameters in either patients or controls. Following successful treatment for the condition, values of Pvi in women with pelvic congestion were significantly reduced, achieving a level similar to that observed in the controls. The observed changes in Pvi suggest that this parameter is intimately associated with the pathophysiology of pelvic congestion. The increase in Pvi, without alterations in other measured microvascular parameters, may be attributable to systemic increases in postcapillary resistance secondary to neutrophil activation. These findings support the notion of systemic microvascular dysfunction in these women.

Microvascular changes in the peripheral microcirculation of women with chronic pelvic pain due to congestion

Objective Pelvic venous congestion is a common finding in women with chronic pelvic pain. While the pathophysiology of this condition is poorly understood, there are clear indications that it involves vascular dysfunction. The present studies sought abnormalities in microvascular function in these patients. Design Prospective longitudinal study. Setting A teaching hospital tertiary referral. Population Eighteen women with pelvic congestion and 13 nomal women. Methods Parameters of microcirculatory function were measured in the calves of women using venous congestion plethysmography during the midfollicular and midluteal phases of the menstrual cycle. The women with pelvic congestion were studied again after treatment for the condition. Main outcome measures Isovolumetric venous pressure, microvascular filtration capacity and limb blood flow. Results Of the measured parameters of microvascular function, only isovolumetric venous pressure (Pvi) was significantly higher in women with congestion when compared to the controls during the same phase of the cycle. There were no menstrual cycle related differences in any of the other measured parameters in either patients or controls. Following successful treatment for the condition, values of Pvi in women with pelvic congestion were significantly reduced, achieving a level similar to that observed in the controls. Conclusion The observed changes in Pvi suggest that this parameter is intimately associated with the pathophysiology of pelvic congestion. The increase in Pvi, without alterations in other measured microvascular parameters, may be attributable to systemic increases in postcapillary resistance secondary to neutrophil activation. These findings support the notion of systemic microvascular dysfunction in these women.

Phasic coronary flow pattern and flow reserve in patients with left bundle branch block and normal coronary arteries

OBJECTIVESThe purpose of this study was to determine whether scintigraphic myocardial perfusion defects in patients with left bundle branch block (LBBB) and normal coronary arteries are related to abnormalities in coronary flow velocity pattern and/or coronary flow reserve.BACKGROUNDSeptal or anteroseptal defects on exercise myocardial perfusion scintigraphy are common in patients with LBBB and normal coronary arteries.METHODSThirteen patients (7 men, age 61 ± 8 years) with LBBB and normal coronary arteries underwent stress thallium-201 scintigraphy and cardiac catheterization. In all patients and in 11 control subjects coronary blood flow parameters were calculated from Doppler measurements of flow velocity in the left anterior descending coronary artery (LAD) before and after adenosine administration.RESULTSThe time to maximum peak diastolic flow velocity was significantly longer both for the seven patients with (134 ± 19 ms) and for the six without (136 ± 7 ms) exercise perfusion defects than for controls (105 ± 12 ms, p < 0.05), whereas the acceleration was slower (170 ± 54, 186 ± 42 and 279 ± 96 cm/s2, respectively, p < 0.05). Coronary flow reserve in the patients with exercise perfusion defects (2.7 ± 0.3) was significantly lower than in those without (3.7 ± 0.5, p < 0.05) or in the control group (3.4 ± 0.5, p < 0.05).CONCLUSIONSPatients with LBBB have an impairment of early diastolic blood flow in the LAD due to an increase in early diastolic compressive resistance resulting from delayed ventricular relaxation. Furthermore, exercise scintigraphic perfusion defects in these patients are associated with a reduced coronary flow reserve, indicating abnormalities of microvascular function in the same vascular territory.

Microvascular functional abnormalities in diabetes: the role of the endothelium

The development of techniques for measuring microvascular pressure, flow and permeability in man has allowed the construct of a pathophysiological framework for the development of diabetic microangiopathy. In insulin dependent disease the abnormalities observed conform to the haemodynamic hypothesis with early elevation of capillary pressure playing a primary role. In non insulin dependent diabetes differences are apparent, supporting the concept that changes in microvascular vasodilatory mechanisms may antedate the emergence of diabetes. Given the crucial role played by the endothelium in the regulation of local microvascular haemodynamics it is not surprising that disturbance of this tissue has been implicated in the pathogenetic process, an assertion supported by mounting experimental evidence suggesting that the nitric oxide pathway is crucially involved.

Microvascular Function in Type 2 (Non‐insulin‐dependent) Diabetes: Improved Vasodilation After One Year of Good Glycaemic Control

Abnormalities of microvascular function may be important in the development of diabetic microangiopathy. The major functional abnormality identified in patients with Type 2 diabetes has been a marked limitation of microvascular vasodilation, which is present from the time of diagnosis. The effects of sustained improvements in glycaemic control on vasodilator capacity in Type 2 diabetes are unknown. Twelve Type 2 diabetic patients were studied prospectively for 1 year after diagnosis. The reduced maximum hyperaemic response to local heating of the foot skin present at the time of diagnosis remained unchanged after 3 months of improved glycaemic control (1.12 +/- 0.56 V at diagnosis vs 1.21 +/- 0.69 V at 3 months, mean +/- SD; p = 0.25), but was improved after 1 year (1.42 +/- 0.91 V; p = 0.04 vs 3 months). The percentage increase in maximum hyperaemia correlated with the percentage decrease in HbA1c (rs = 0.53, p = 0.04). These results suggest that the early microvascular abnormalities demonstrated in Type 2 diabetes are potentially reversible and provide a further reason for striving for optimal glycaemic control in this patient group.

Do neutrophils contribute to myocardial stunning?

Although removal of neutrophils from the arterial blood by mechanical filtration has been reported to prevent or reduce the severity of myocardial stunning caused by a 15 minute coronary artery occlusion in the dog, neutrophil filtration does not protect against myocardial dysfunction following a 10-minute occlusion. Nonfilter methods to reduce neutrophil numbers or effectiveness with anti-neutrophil serum, monoclonal anti-CD11b antibodies, or the lipoxygenase inhibitor nafazatrom fail to modify myocardial dysfunction after brief ischemia, even though they effectively reduce infarct size after more prolonged ischemia. The brief durations of ischemia required to produce myocardial stunning but to avoid necrosis are insufficient to produce local activation of complement, formation of chemotactic factors, or activation or infiltration of neutrophils. Microvascular plugging with neutrophils cannot be demonstrated in stunned myocardium, and abnormalities of microvascular function can be dissociated from impaired postischemic myocardial function. Based on the weight of accumulated evidence, neutrophils appear to have no important role in the production of stunned myocardium.

RENAL AND HEPATIC MICROVASCULAR VOLUMES DURING THE DEVELOPMENT OF GLYCEROL-INDUCED RENAL FAILURE

Abnormalities of microvascular function have been implicated as a potential pathogenetic mechanism in the development of experimental acute renal failure. To non-invasively examine alterations in renal microvascular volume during the initiation of glycerol-induced acute renal failure (ARF) in rats, we have employed the combination of a non-renally excreted, intravascularly maintained, experimental contrast agent (perfluoroctylbromide) and CT scanning for contrast agent spatial quantitation. We scanned normal rats and early ARF-affected rats, prior to and following perfluoroctylbromide administration and obtained CT values pre(CT)- and post(CT')- contrast for kidney (k), liver (1), and blood (b), and devised the following ratios as indicators of relative microvascular volume (mv): mv(k) = CT'(k) – CT(k)/CT'(b) – CT(b) mv(1) = CT'(1) – CT(1)/CT'(b) – CT(b) We intend to address the validity of these equations as a measure of microvascular volume and apply them to the relationship between the amount of time following the induction of ARF and alterations from normal in renal and hepatic microvascular volumes. Further correlations between these events and the onset of histologic changes of ARF also will be discussed. Dr. Hillman is a Hartford Foundation Fellow. This work supported in part by grants from the Arizona Heart Association and Arizona Kidney Foundation. We are grateful to Dr. David Long for supplying the perfluoroctylbromide.