Endothelium-dependent Microvascular Function Research Articles

Rethinking False Positive Exercise Electrocardiographic Stress Tests by Assessing Coronary Microvascular Function

BackgroundExercise electrocardiographic stress testing (EST) has historically been validated against the demonstration of obstructive coronary artery disease. However, myocardial ischemia can occur because of coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease. ObjectivesThe aim of this study was to assess the specificity of EST to detect an ischemic substrate against the reference standard of coronary endothelium-independent and endothelium-dependent microvascular function in patients with angina with nonobstructive coronary arteries (ANOCA). MethodsPatients with ANOCA underwent invasive coronary physiological assessment using adenosine and acetylcholine. CMD was defined as impaired endothelium-independent and/or endothelium-dependent function. EST was performed using a standard Bruce treadmill protocol, with ischemia defined as the appearance of ≥0.1-mV ST-segment depression 80 ms from the J-point on electrocardiography. The study was powered to detect specificity of ≥91%. ResultsA total of 102 patients were enrolled (65% women, mean age 60 ± 8 years). Thirty-two patients developed ischemia (ischemic group) during EST, whereas 70 patients did not (nonischemic group); both groups were phenotypically similar. Ischemia during EST was 100% specific for CMD. Acetylcholine flow reserve was the strongest predictor of ischemia during exercise. Using endothelium-independent and endothelium-dependent microvascular dysfunction as the reference standard, the false positive rate of EST dropped to 0%. ConclusionsIn patients with ANOCA, ischemia on EST was highly specific of an underlying ischemic substrate. These findings challenge the traditional belief that EST has a high false positive rate.

Coronary microvascular function in male physicians with burnout and job stress: an observational study

BackgroundAs a professional group, physicians are at increased risk of burnout and job stress, both of which are associated with an increased risk of coronary heart disease that is at least as high as that of other professionals. This study aimed to examine the association of burnout and job stress with coronary microvascular function, a predictor of major adverse cardiovascular events.MethodsThirty male physicians with clinical burnout and 30 controls without burnout were included. Burnout was assessed with the Maslach Burnout Inventory and job stress with the effort-reward imbalance and overcommitment questionnaire. All participants underwent myocardial perfusion positron emission tomography to quantify endothelium-dependent (cold pressor test) and endothelium-independent (adenosine challenge) coronary microvascular function. Burnout and job stress were regressed on coronary flow reserve (primary outcome) and two additional measures of coronary microvascular function in the same model while adjusting for age and body mass index.ResultsBurnout and job stress were significantly and independently associated with endothelium-dependent microvascular function. Burnout was positively associated with coronary flow reserve, myocardial blood flow response, and hyperemic myocardial blood flow (r partial = 0.28 to 0.35; p-value = 0.008 to 0.035). Effort-reward ratio (r partial = − 0.32 to − 0.38; p-value = 0.004 to 0.015) and overcommitment (r partial = − 0.30 to − 0.37; p-value = 0.005 to 0.022) showed inverse associations with these measures.ConclusionsIn male physicians, burnout and high job stress showed opposite associations with coronary microvascular endothelial function. Longitudinal studies are needed to show potential clinical implications and temporal relationships between work-related variables and coronary microvascular function. Future studies should include burnout and job stress for a more nuanced understanding of their potential role in cardiovascular health.

Abstract 17343: Coronary Microvascular Function in Physician Burnout and Job Stress

Background: As a professional group, physicians are at increased risk of burnout and job stress, both of which are associated with an increased risk of coronary heart disease that seems more prevalent among male than female physicians. Aim: This study aimed to examine the association of burnout and job stress with coronary microvascular function, a predictor of major adverse cardiovascular events. Methods: Thirty male physicians with clinical burnout and 30 controls without burnout were included. Burnout was assessed with the Maslach Burnout Inventory and job stress with the effort-reward imbalance and overcommitment questionnaire. All participants underwent myocardial perfusion positron emission tomography to quantify endothelium-dependent (cold pressor test) and endothelium-independent (adenosine challenge) coronary microvascular function. Burnout and job stress were regressed on measures of coronary microvascular function in the same model while adjusting for age and body mass index. Results: Burnout and job stress had significant and independent effects on endothelium-dependent microvascular function. Burnout was positively associated with coronary flow reserve, myocardial blood flow (MBF) response, and hyperemic MBF (r partial: 0.29 to 0.35; p-value: 0.008 to 0.027). Effort-reward ratio (r partial: -0.32 to -0.34; p-value: 0.009 to 0.017) and overcommitment (r partial: -0.29 to -0.35; p-value: 0.008 to 0.027) showed inverse associations with these measures. Conclusions: In male physicians, burnout and high job stress showed opposite effects on coronary microvascular endothelial function. Longitudinal studies are needed to show potential clinical implications. Future studies should include burnout and job stress for a more nuanced understanding of their potential impact on cardiovascular health.

The deleterious effects of acute hypoxia on microvascular and large vessel endothelial function.

What is the central question of this study? The aim was primarily to determine the effect of hypoxia on microvascular function and secondarily whether superior cardiorespiratory fitness is protective against hypoxia-induced impairment in vascular function. What is the main finding and its importance? Hypoxia reduced endothelium-dependent but not endothelium-independent microvascular function. The extent of impairment was twofold higher in the microcirculation compared with the large blood vessels. This study suggests that individuals with superior cardiorespiratory fitness might preserve microvascular function in hypoxia. These findings highlight the sensitivity of the microvascular circulation to hypoxia. Hypoxia is associated with diminished bioavailability of the endothelium-derived vasodilator, nitric oxide (NO). Diminished NO bioavailability can have deleterious effects on endothelial function. The endothelium is a heterogeneous tissue; therefore, a comprehensive assessment of endothelial function is crucial to understand the significance of hypoxia-induced endothelial dysfunction. We hypothesized that acute hypoxia would have a deleterious effect on microvascular and large vessel endothelial function. Twenty-nine healthy adults [24(SD = 4 )years of age] completed normoxic and hypoxic [inspired O2 fraction=0.209] trials in this double-blinded, counterbalanced crossover study. After 30min, we assessed the laser Doppler imaging-determined perfusion response to iontophoresis of ACh as a measure of endothelium-dependent microvascular function and iontophoresis of sodium nitroprusside as a measure of endothelium-independent microvascular function. After 60min, we assessed brachial flow-mediated dilatation as a measure of large vessel endothelial function. Thirty minutes of hypoxia reduced endothelium-dependent microvascular function determined by the perfusion response to ACh (median difference (x̃∆)=-109% {interquartile range: 542.7}, P<0.05), but not endothelium-independent microvascular function determined by the perfusion response to sodium nitroprusside (x̃∆ = 69% {interquartile range: 453.7}, P=0.6). In addition, 60min of hypoxia reduced allometrically scaled flow-mediated dilatation compared with normoxia ( [95% CI = -1.80, -0.58 (Confidence Intervals)]%, P<0.001). The decrease in microvascular endothelial function was associated with cardiorespiratory fitness (r =0.45, P=0.02). In conclusion, acute exposure to normobaric hypoxia significantly reduced endothelium-dependent vasodilatory capacity in small and large vessels. Collectively, these findings highlight the sensitivity of the microvascular circulation to hypoxic insult, particularly in those with poor cardiorespiratory fitness.

Lower endothelium-dependent microvascular function in adult breast cancer patients receiving radiation therapy

PurposeCancer patients with a history of radiotherapy are at an increased risk of ischemic heart disease. Preclinical animal studies demonstrate markedly impaired acetylcholine (ACh)-mediated endothelium-dependent vasorelaxation within days to weeks post-irradiation, however, whether microvascular function is affected in the intact human circulation during cancer radiation therapy has yet to be determined.Materials and methodsUsing laser-Doppler flowmetry, microvascular endothelium-dependent and independent responses were evaluated through iontophoresis of acetylcholine (ACh) (part 1, n = 7) and sodium nitroprusside (SNP) (part 2, n = 8), respectively, in women currently receiving unilateral chest adjuvant radiation therapy for breast cancer. Measurements were performed at the site of radiation treatment and at a contralateral control, non-radiated site. Cutaneous vascular conductance (CVC) was calculated by normalizing for mean arterial pressure.Results and ConculsionsIn part 1, patients received an average radiation dose of 2104 ± 236 cGy. A significantly lower peak ACh-mediated endothelium-dependent vasodilation was observed within the radiated microvasculature when compared to non-radiated (radiated: 532 ± 167%, non-radiated 1029 ± 263%; P = 0.02). In part 2, the average radiation dose received was 2251 ± 196 cGy. Iontophoresis of SNP elicited a similar peak endothelium-independent vasodilator response in radiated and non-radiated tissue (radiated: 179 ± 58%, non-radiated: 310 ± 158; P = 0.2). The time to 50% of the peak response for ACh and SNP was similar between radiated and non-radiated microvasculature (P < 0.05). These data provide evidence of early endothelium-dependent microvascular dysfunction in cancer patients currently receiving chest radiation and provide the scientific premise for future work evaluating coronary endothelial function and vasomotor reactivity using more detailed and invasive procedures.

Weight change and sulfonylurea therapy are related to 3\xa0year change in microvascular function in people with type 2 diabetes

Aims/hypothesisAlthough cardiovascular disease is the biggest cause of death in people with diabetes, microvascular complications have a significant impact on quality of life and financial burden of the disease. Little is known about the progression of microvascular dysfunction in the early stages of type 2 diabetes before the occurrence of clinically apparent complications. We aimed to explore the determinants of endothelial-dependent and -independent microvascular function progression over a 3 year period, in people with and without both diabetes and few clinical microvascular complications.MethodsDemographics were collected in 154 participants with type 2 diabetes and in a further 99 participants without type 2 diabetes. Skin microvascular endothelium-dependent response to iontophoresis of acetylcholine and endothelium-independent responses to sodium nitroprusside were measured using laser Doppler fluximetry. All assessments were repeated 3 years later.ResultsPeople with type 2 diabetes had impaired endothelial-dependent microvascular response compared with those without (AUC 93.9 [95% CI 88.1, 99.4] vs 111.9 [102.3, 121.4] arbitrary units [AU] × min, p < 0.001, for those with vs without diabetes, respectively). Similarly, endothelial-independent responses were attenuated in those with diabetes (63.2 [59.2, 67.2] vs 75.1 [67.8, 82.4] AU × min, respectively, p = 0.002). Mean microvascular function declined over 3 years in both groups to a similar degree (pinteraction 0.74 for response to acetylcholine and 0.69 for response to sodium nitroprusside). In those with diabetes, use of sulfonylurea was associated with greater decline (p = 0.022 after adjustment for co-prescriptions, change in HbA1c and weight), whereas improving glycaemic control was associated with less decline of endothelial-dependent microvascular function (p = 0.03). Otherwise, the determinants of microvascular decline were similar in those with and without diabetes. The principal determinant of change in microvascular function in the whole population was weight change over 3 years, such that those that lost ≥5% weight had very little decline in either endothelial-dependent or -independent function compared with those that were weight stable, whereas those who gained weight had a greater decline in function (change in endothelial-dependent function was 1.2 [95% CI −13.2, 15.7] AU × min in those who lost weight; −15.8 [−10.5, −21.0] AU × min in those with stable weight; and −37.8 [−19.4, −56.2] AU × min in those with weight gain; ptrend < 0.001). This association of weight change with change in endothelial function was driven by people with diabetes; in people without diabetes, the relationship was nonsignificant.Conclusions/interpretationOver 3 years, physiological change in weight was the greatest predictor of change in microvascular function.

5879Coronary microvascular dysfunction is associated with poor glycemic control in women with diabetes presenting with chest pain and non-obstructive coronary artery disease

Abstract Background Patients with type 2 diabetes are at an increased risk of cardiovascular events compared to individuals without diabetes. The role glycemic control plays in reducing cardiovascular risk remains uncertain. Coronary microvascular dysfunction (CMD) is more frequent in women compared to men, is prevalent in patients with type 2 diabetes and is linked to adverse cardiovascular events. We compared the association between CMD and glycemic control across sexes in patients with chest pain and non-obstructive coronary artery disease (CAD). Methods Patients with chest pain who were found to have non-obstructive CAD (stenosis &lt;40%) at angiography underwent an invasive assessment of endothelial-independent and endothelial–dependent coronary microvascular function. Using a Doppler guidewire, endothelial-independent microvascular function was assessed by measuring the coronary flow velocity in response to intracoronary adenosine and comparing this to baseline to calculate the coronary flow reserve ratio (CFRAdn). A CFRAdn ≤2.5 was considered abnormal. Endothelial-dependent microvascular function was assessed by measuring the percent change in coronary blood flow in response to intracoronary infusions of acetylcholine (%ΔCBFAch), with a %ΔCBFAch ≤50% considered abnormal. Patients were classified as having normal versus abnormal CFRAdn and %ΔCBFAch. Measurements of HbA1c and fasting serum glucose were obtained at the time of catheterization and compared between groups after stratification by sex. Results Between 1993 and 2012, 1,469 patients (mean age 50.4 years, 35% male) underwent coronary angiography and invasive testing for CMD, of which 129 (8.8%) had type 2 diabetes. Fifty one (39.5%) had an abnormal %ΔCBFAch and 49 (38.0%) had an abnormal CFRAdn. Conventional cardiovascular risk factors did not vary significantly between groups. Females with an abnormal CFRAdn or abnormal %ΔCBFAch had a significantly higher HbA1c compared to those with a normal CFRAdn or %ΔCBFAch respectively: HbA1c % (standard deviation) 7.4 (2.1) vs. 6.5 (1.1), p=0.035 and 7.3 (1.9) vs. 6.4 (1.2), p=0.022, respectively. Females with an abnormal CFRAdn had significantly higher fasting serum glucose concentrations compared to those with a normal CFRAdn: fasting serum glucose mg/dL (standard deviation) 144.4 (55.6) vs. 121.9 (28.1), p=0.035. These effects were not observed in men. Amongst female diabetics, a higher HbA1c was significantly associated with any CMD after adjusting for covariates: odds ratio (95% confidence interval) 1.69 (1.01 – 2.86) p=0.049; and a fasting serum glucose &gt;140 mg/dL was significantly associated with an abnormal CFRAdn, 4.28 (1.43–12.81). Conclusion Poor glycemic control is associated with CMD in females with diabete who present with chest pain and non-obstructive CAD. These findings highlight the importance of sex-specific risk stratification models and treatment strategies when managing cardiovascular risk in diabetics. Acknowledgement/Funding Mayo Foundation

Exploring the microcirculatory effects of an exercise programme including aerobic and resistance training in people with limited cutaneous systemic sclerosis

Purpose of the studyHigh intensity interval training (HIIT) is able to improve the endothelial-dependent microvascular function is people with limited cutaneous systemic sclerosis (lcSSc). Resistance training (RT) alone has shown significant improvements in the function of the vasculature; moreover, a combination of aerobic and RT have shown both in the past and recently to significantly improve the vascular function and the microcirculation. Therefore, the purpose of this study is to explore the effectiveness of a combined exercise protocol (aerobic and resistance training) on microvascular function in people with lcSSc. MethodsThirty-two lcSSc patients (66.5 ± 12 years old) were randomly allocated in two groups (exercise and control group). The exercise group underwent a 12-week exercise programme twice per week. All patients performed the baseline, three- and six-month follow up measurements where microvascular function, transcutaneous oxygen tension (ΔTcpO2) and body composition were assessed. ResultsThe time to peak endothelial-dependent reactivity was significantly improved (91 ± 42 s, d = 1.06, p = 0.007) when compared to control group after the exercise intervention. Endothelial-independent function was also significantly improved (3.16 ± 2, d = 1.17, p = 0.005) when compared to the control group. Baseline (5.71 ± 4.4, p < 0.05)) and peak (15.4 ± 7.5, p < 0.05) transcutaneous oxygen pressure were also significantly improved compared to the control group. ConclusionsOur results suggest that a combined exercise protocol (aerobic and RT) was effective in improving endothelial-dependent reactivity in people with lcSSc. The next step would be to explore its clinical- and cost- effectiveness. Therefore, we recommend a large, community-based intervention against standard pharmacotherapy only, which would assess these important factors and support a change in therapeutic protocols and guidelines for this clinical population.Trial registrationClinicalTrials.gov (NCT number): NCT03058887, February 23, 2017, https://clinicaltrials.gov/ct2/show/NCT03058887?term=NCT03058887&rank=1

Coronary microvascular dysfunction is associated with poor glycemic control amongst female diabetics with chest pain and non-obstructive coronary artery disease

BackgroundPatients with type 2 diabetes mellitus are at an increased risk of adverse cardiovascular events compared to those without diabetes. The timing, relative to disease onset, and degree of glycemic control that reduces the risk of adverse cardiovascular events remains uncertain. Coronary microvascular dysfunction is prevalent in patients with type 2 diabetes mellitus and is linked to adverse cardiovascular events. We assessed the association between endothelial-dependent and endothelial-independent coronary microvascular dysfunction and glycemic control in patients presenting with chest pain and nonobstructive coronary disease at angiography.MethodsPatients presenting with chest pain and found to have non-obstructive CAD (stenosis < 40%) at angiography underwent an invasive assessment of endothelial-independent and endothelial –dependent microvascular function. Endothelial-independent microvascular function was assessed by comparing the coronary flow velocity, measured using a Doppler guidewire, in response to intracoronary infusion of adenosine to calculate the coronary flow reserve ratio in response to adenosine (CFRAdn Ratio). A CFRAdn Ratio ≤ 2.5 was considered abnormal. Endothelial-dependent microvascular function was assessed by measuring the percent change in coronary blood flow in response to intracoronary infusions of acetylcholine (%ΔCBFAch), and microvascular endothelial dysfunction defined as a %ΔCBFAch of ≤ 50%. Patients were classified by normal versus abnormal CFRAdn Ratio and %ΔCBFAch. Measurements of HbA1c and fasting serum glucose were obtained prior to catheterization and compared between groups.ResultsBetween 1993 and 2012, 1469 patients (mean age 50.4 years, 35% male) underwent coronary angiography and invasive testing for coronary microvascular dysfunction, of which 129 (8.8%) had type 2 diabetes. Fifty-one (39.5%) had an abnormal %ΔCBFAch and 49 (38.0%) had an abnormal CFRAdn Ratio. Conventional cardiovascular risk factors and cardiovascular or diabetic medication use did not vary significantly between groups. Females with an abnormal CFRAdn Ratio or abnormal %ΔCBFAch had a significantly higher HbA1c compared to patients with a normal CFRAdn Ratio or %ΔCBFAch respectively: HbA1c % (standard deviation) 7.4 (2.1) vs. 6.5 (1.1), p = 0.035 and 7.3 (1.9) vs. 6.4 (1.2), p = 0.022, respectively. Female patients with an abnormal CFRAdn Ratio had significantly higher fasting serum glucose concentrations compared to those with a normal CFRAdn Ratio: fasting serum glucose mg/dL (standard deviation) 144.4 (55.6) vs. 121.9 (28.1), p = 0.035. This was not observed in men. Amongst female diabetics, a higher HbA1c was significantly associated with any coronary microvascular dysfunction both in a univariate and multivariate analysis: odds ratio (95% confidence interval) 1.69 (1.01–2.86) p = 0.049; and a fasting serum glucose > 140 mg/dL was significantly associated with an abnormal CFRAdn Ratio, 4.28 (1.43–12.81).ConclusionPoor glycemic control is associated with coronary microvascular dysfunction amongst female diabetics presenting with chest pain and non-obstructive CAD. These findings highlight the importance of sex specific risk stratification models and treatment strategies when managing cardiovascular risk amongst diabetics. Further studies are required to identify additional risk prevention tools and therapies targeting microvascular dysfunction as an integrated index of cardiovascular risk.

Prevalence of Microvascular and Endothelial Dysfunction in the Nonculprit Territory in Patients With Acute Myocardial Infarction.

Approximately half of the patients presenting with ST-segment-elevation myocardial infarction (STEMI) have multivessel disease. The physiology of the nonculprit artery has not been thoroughly studied to date. We sought to characterize the coronary physiology of the nonculprit artery in the early phase after STEMI and determine the real prevalence of microvascular and endothelial dysfunction. Patients with STEMI and another coronary artery lesion in a different territory were prospectively included in an observational single-center study. The protocol took place after revascularization of the culprit artery and comprised 3 phases: first, epicardial endothelial functional assessment using intracoronary acetylcholine; second, epicardial severity quantification based on fractional flow reserve, and nonendothelial microvascular function with coronary flow reserve and the index of microvascular resistance; third, endothelium-dependent microvascular function assessment based on the endothelial coronary flow reserve. Eighty-four patients were included. Mean age was 62±10 years, and 86.9% were men. Only 6 subjects had a nonpathological study: macrovascular endothelial dysfunction was present in 60% of the patients; fractional flow reserve ≤0.8, coronary flow reserve <2, and index of microvascular resistance >25 were evident in 34%, 37%, and 28% of the subjects respectively; and microvascular endothelial dysfunction (endothelial coronary flow reserve <1.5) was observed in 44%. In hospital-mortality was 0%, and no major complications occurred. At 6-month follow-up, there were no events related to the nonculprit artery. Microvascular and endothelial dysfunction in the nonculprit artery territory in patients with STEMI are very common. In 93% of the patients, we found functional abnormalities. Acetylcholine administration in the early phase post-STEMI in patients with multivessel disease is safe.

Sitting time is negatively related to microvascular endothelium-dependent function in rheumatoid arthritis

BackgroundSedentary behaviour is linked to increased cardiovascular disease risk in Rheumatoid Arthritis (RA), but the biological processes underlying this relationship are not understood. ObjectivesTo investigate the cross-sectional associations of habitual sedentary behaviour, with endothelial function in RA. MethodsSixty-eight RA patients (Mage = 55 ± 12 years) underwent Laser Doppler Imaging with iontophoresis, to assess microvascular endothelium-dependent (acetylcholine, ACh) and endothelium-independent (sodium nitroprusside, SNP) function. Large-vessel endothelium-dependent and endothelium-independent functions were measured via flow-mediated dilation (FMD) and glyceryl trinitrate dilation (GTN), respectively. Habitual sedentary behaviour (hours/week sitting) was self-reported (International Physical Activity Questionnaire). ResultsRegressions revealed sitting time significantly negatively predicted microvascular endothelium-dependent function (ACh, unstandardizedβ = −3.25, p = .02, 95% CI [−6.07, −.42], R2 = 0.06), but did not associate with other endothelial function outcomes (SNP, FMD, GTN). ConclusionHabitual sedentary behaviour (sitting time) appears to be adversely linked to microvascular endothelium-dependent function among people living with RA.

Penile microvascular endothelial function in hypertensive patients: effects of acute type 5 phosphodiesterase inhibition

The primary aim of this study was to evaluate penile endothelial microvascular function in patients with primary arterial hypertension and age-matched normotensive subjects using laser speckle contrast imaging (LSCI). Additionally, we analyzed the acute penile microvascular effects induced by oral phosphodiesterase type 5 inhibitor (sildenafil; SIL) administration. Endothelium-dependent microvascular reactivity was evaluated in the penises and forearms of hypertensive patients (aged 58.8±6.6 years, n=34) and age-matched healthy volunteers (n=33) at rest and 60 min following oral SIL (100 mg) administration. LSCI was coupled with cutaneous acetylcholine (ACh) iontophoresis using increasing anodal currents. Basal penile cutaneous vascular conductance (CVC) values were not significantly different between control subjects and hypertensive individuals. Penile CVC values increased significantly after SIL administration in control (P<0.0001) and hypertensive (P<0.0001) subjects. Peak CVC values were not different between the two groups during penile ACh iontophoresis before SIL administration (P=0.2052). Peak CVC values were higher in control subjects than in hypertensive subjects after SIL administration (P=0.0427). Penile endothelium-dependent microvascular function is, to some extent, preserved in patients presenting with primary arterial hypertension under effective anti-hypertensive treatment. LSCI may be a valuable non-invasive tool for the evaluation of penile vascular responses to phosphodiesterase type 5 inhibitor.

PP.12.06] PENILE MICROVASCULAR ENDOTHELIAL FUNCTION IN HYPERTENSIVE PATIENTS

Objective: The primary aim of this study was to test penile endothelial microvascular function in patients with treated arterial hypertension, compared to an age-matched group of normotensive subjects using laser speckle contrast imaging (LSCI). Additionally, we tested the acute penile microvascular effects induced by the oral administration of the phosphodiesterase type 5 inhibitor sildenafil citrate (SIL). Design and method: Endothelium-dependent penile microvascular reactivity of hypertensive patients (aged 58.8 ± 6.6 years, n = 34) and age-matched healthy volunteers (n = 33) was evaluated at rest and 60 minutes following oral administration of SIL (100 mg). LSCI was coupled with the cutaneous iontophoresis of acetylcholine (ACh) using increasing anodal currents. The measurements of skin blood flow (arbitrary perfusion units, APU) were divided by values of mean arterial pressure to give the cutaneous vascular conductance (CVC) in APU/mmHg. Results: Office systolic arterial pressure was 122.6 ± 8.8 and 136.7 ± 13.8 mmHg for control and hypertensive subjects, respectively (P < 0.0001); diastolic arterial pressure was 79.3 ± 6.6 and 86.7 ± 7.6 mmHg for control and hypertensive subjects, respectively (P < 0.0001). The basal values of skin microvascular flow (APU) in the penis before (P = 0.5808) and after SIL (P = 0.4256) were similar in the control and hypertensive subjects. Penile baseline microvascular flow was significantly increased after SIL in control (P = 0.0006) and also in hypertensive (P = 0.0038) subjects, compared to basal values before SIL. The basal values of CVC in the penis before (P = 0.0590) and after (P = 0.0857) SIL in the control and hypertensive participants were not significantly different. The peak values of CVC during iontophoresis of ACh in the penis before SIL were of 0.62 (0.44–0.91) and 0.50 (0.33–0.79) APU/mmHg in the control and hypertensive participants, respectively (P = 0.2052). After administration of SIL, the peak values of CVC during iontophoresis of ACh in the penis were of 0.88 (0.66–1.12) and 0.69 (0.56–0.84) APU/mmHg in the control and hypertensive participants, respectively (P = 0.0427). Conclusions: Penile endothelium-dependent microvascular function was similar in hypertensive patients and healthy controls. Nevertheless, the response to the acute administration of SIL was higher in the controls than in hypertensive patients.

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.

In vivo microvascular and macrovascular endothelial function is not associated with circulating dimethylarginines in patients with rheumatoid arthritis: a prospective analysis of the DRACCO cohort

ABSTRACTObjectives: To examine associations between asymmetric (ADMA), symmetric dimethylarginine (SDMA) and ADMA:SDMA ratio with assessments of endothelial function and coronary artery perfusion in RA patients.Methods: ADMA and SDMA levels were measured in 197 RA individuals [144 (77.4%) females, median age: 66 years (quartiles: 59–73)]. Patients underwent assessments of microvascular endothelium-dependent and endothelium-independent function, macrovascular endothelium-dependent and endothelium-independent function and vascular morphology (pulse wave analysis, carotid intima-media thickness (cIMT), and carotid plaque). Coronary perfusion was assessed by subendocardial viability ratio (SEVR).Results: SEVR correlated with SDMA (r = 0.172, p = 0.026) and ADMA:SDMA (r = −0.160, p = 0.041) in univariable analysis, but not in multivariable analysis accounting for confounding factors. Neither ADMA:SDMA ratio nor SDMA were significantly correlated with microvascular or macrovascular endothelial function, or with arterial stiffness and cIMT. Within subgroup of patients (n = 26) with high inflammatory markers, a post-hoc analysis showed that SDMA and the ADMA:SDMA ratio were significantly associated with endothelium-dependent microvascular function in univariable analysis, with Pearson’s r correlation coefficients of −0.440 (p = 0.031) and 0.511 (p = 0.011), respectively. Similar finding were established between ADMA:SDMA ratio and arterial stiffness in univariable analysis, with Pearson’s r of 0.493, (p = 0.024).Conclusion: Dimethylarginines were not found to be significantly associated with several assessments of vascular function and morphology in patients with RA, however, post-hoc analysis indicates that there may be associations in patients with raised inflammatory markers. Our results suggest that dysregulated NO metabolism may not be the sole mechanism for the development of preclinical atherosclerosis in RA.

Abstract 17128: Pathophysiology of Coronary Artery Disease in Hiv-infected Patients: Dissociation Between Anatomy and Function

Introduction: Numerous reports suggest, among HIV+ patients (pts), an increased rate of acute coronary syndrome and cardiac death. Several data suggest that endothelial dysfunction is a major mechanisms in the development of coronary atherosclerosis in non-HIV infected patients. Hypothesis: The aim of our study is to assess coronary microvascular function using Doppler-flow wire in HIV+ patients in therapy with HAART. Methods: Thirteen HIV-infected patients were enrolled from the Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences of the “Sapienza” University of Rome (Italy). The main inclusion criteria were: Framingham risk score &lt;10%, absence of metabolic syndrome (according to the definition of Adult Treatment Panel III e ATPIII12), negative echocardiographic and ECG stress-test and negative for anti-HCV antibodies. Diagnostic coronary angiography was performed via percutaneous radial approach. Microvascular function was assessed by measuring coronary flow velocity reserve (CFR). Intracoronary functional tests were performed to evaluate both endothelium-dependent microvascular function [via intracoronary (IC) infusion of acetylcholine (2.5[[Unable to Display Character: &amp;#8211;]]10 μg)] and non-endothelium-dependent microvascular function [via IC infusion of adenosine (5 μg) ]. Results: All the patients presented a Framingham risk score &lt;10%. The medium age was 53.3±4.1 years. The mean duration of highly active antiretroviral therapy was 12.9±2.4 years. Thirteen patients presented 23 coronary atherosclerotic plaques; while endothelium and non endothelium-dependent microvascular function was quite normal in our population (CFR after adenosine 2.37±0.4; CFR after Achetylcholine 2.43±0.4). Conclusion: Microvascular function is not compromised in HIV + pts who presented coronary atherosclerotic plaque. Microvascular dysfunction, involved in pathophysiology of coronary artery disease in general population, seems to be not implicated in coronary atherosclerosis in HIV + pts. These data suggest a peculiar pathophysiological mechanisms for HIV related atherosclerosis.

Abstract 18339: Weight Loss with Low Carbohydrate Diets Improves Flow Induced Vasodilation in Resistance Arteries

Introduction: Obesity is associated with microvascular dysfunction and reduced nitric oxide (NO). We tested the hypothesis that NO-dependent, flow induced vasodilation in microvessels is improved by low carbohydrate diets designed for weight loss. Methods: Obese female adults (BMI = 32.0 ± 0.6 kg/m 2 , pre &amp; post, n=22) were randomly assigned to a low carbohydrate (LC) diet for weight loss (LCWL, n=11, 500 calorie/day deficit). All meals were prepared for 6 weeks (10% carbohydrate, 30% protein, 60% fat). Resistance arteries (RAs, internal diameter of 16021 μm, n=22) were dissected from gluteal subcutaneous fat biopsies at weeks 0 (pre) and 6 (post). Vessels were cannulated and exposed to pressure gradients (Δ10-Δ100 cmH 2 O), with or without L-NAME (10 -4 M, inhibitor of eNOS), PEG-catalase (PEG-CAT, 500 Units/ml, scavenger of H 2 O 2 ), indomethacin (INDO, 10 -5 M, inhibitor of cyclooxygenase), or pioglitazone (PIOG, 10 -5 M, PPARγ agonist) and to papaverine (10 -4 M), pre and post LC. NO or H 2 O 2 in RAs was measured by fluorescence microscopy. Results: LC diets reduced BMI (post 32.7±0.8% vs. pre 31.4±1.0%, p&lt;0.01), and increased flow-induced vasodilation (FID, post 81 ± 3% vs. pre 63 ± 4%, at Δ100 cmH 2 O (p&lt;0.01) that was reduced by L-NAME and PEG-CAT (p&lt;0.05). Consistently, vascular NO (fluorescence ratio: 1.5 ± 0.3, post vs. pre, p&lt;0.05) and H 2 O 2 (2.6 ± 1.2, p&lt;0.05) were increased with flow, and inhibited by L-NAME and PEG-CAT, respectively. INDO reduced FID in post, less (p&lt;0.05) than in pre LC. There was no effect of pioglitazone on FID both in pre and in post (p&gt;0.05). Endothelium independent responses to papaverine were similar in pre and post LC. Conclusion: We found that after 6 weeks of WL on low carbohydrate diet, 1) BMI was reduced, and microvascular vasodilator reactivity was improved; 2) microvascular NO and H 2 O 2 generation were increased; and 3) there was no effect of pioglitazone on FID in resistance arteries. These data indicate that weight reduction on low carbohydrate diet is critical for improved and endothelium-dependent microvascular function. NIH ( R01HL095701 ).

Cutaneous microvascular endothelium‐dependent vasodilation is impaired in young obese subjects (678.4)

Cutaneous microvascular endothelium dependent vasodilation is impaired in young obese subjects Jordan C. Patik, Kevin M. Christmas, and R. Matthew Brothers Environmental and Autonomic Physiology Laboratory, Department of Kinesiology and Health Education, University of Texas at Austin Microvascular dysfunction is a precursor to a variety of cardiovascular diseases and contributes to insulin resistance and type II diabetes. Obese individuals are at a greater risk for the development of these aforementioned conditions relative to their lean counterparts. The purpose of this study was to asses endothelium dependent microvascular function in young, otherwise healthy, obese individuals. Specifically, we tested the hypothesis that the cutaneous microvascular response to intradermal administration of methacholine (MCh) would be blunted in obese relative to lean individuals. 6 young obese and 5 young lean individuals (Age: 24±2.2 vs. 25±1.18 years P&gt;0.05; BMI: 34.96±1.89 vs. 22.24±0.84 kg/m2, P&lt;0.001) participated in this study. Microvascular function was assessed using laser Doppler flowmetry to calculate cutaneous vascular conductance over a range of MCh concentrations infused through microdialysis membranes. Dose response curves were constructed to determine the effective concentration that elicits 50% of maximal conductance (EC50). Young obese subjects had significantly blunted EC50 responses to MCh infusion relative to the lean individuals (Obese: ‐3.173±0.526 vs. Lean: ‐4.875 ±0.199 log molar concentration of MCh, P = 0.02). Our preliminary results support the hypothesis that impaired endothelium dependent vasodilation is present in relatively young obese individuals prior to the development of obesity related disease.

The role of inflammation and cardiovascular disease risk on microvascular and macrovascular endothelial function in patients with rheumatoid arthritis: a cross-sectional and longitudinal study

IntroductionRheumatoid arthritis (RA) is associated with an increased risk for cardiovascular disease (CVD), and it has been postulated that RA disease-related inflammation contributes to endothelial dysfunction. The aim of the present work was to examine predictors (RA-related and CVD risk factors) and anti-tumor necrosis factor-alpha (anti-TNF-α) treatment effects on endothelial function in different vascular beds.MethodsMicrovascular endothelial function (laser Doppler imaging with iontophoresis of acetylcholine and sodium-nitroprusside), and macrovascular endothelial function (flow-mediated dilatation and glyceryl-trinitrate-mediated dilatation) were analyzed in parallel with disease activity. Individual CVD risk factors and global CVD risk were assessed cross-sectionally in 99 unselected RA patients and longitudinally (baseline, 2 weeks, and 3 months) in 23 RA patients commencing anti-TNF-α therapy.ResultsIn this cross-sectional study, regression analyses revealed that markers of RA disease-related inflammation were not associated with microvascular or macrovascular endothelium-dependent function (P > 0.05); global CVD risk inversely correlated with microvascular endothelium-dependent function (P < 0.01) and with macrovascular endothelium-independent function (P < 0.01). In the longitudinal study, only microvascular endothelium-dependent function showed an improvement after 2 weeks of anti-TNF-α treatment when compared with baseline (437% ± 247% versus 319% ± 217%; P = 0.001), but no association was evident between change in endothelial function and change in inflammatory markers.ConclusionsClassical CVD risk may influence endothelial function more than disease-related markers of inflammation in RA. Classical CVD risk factors and anti-TNF-α medication have different effects on microvascular and macrovascular endothelial function, suggesting that combined CVD-prevention approaches may be necessary. Prospective studies examining whether assessments of vascular function are predictive of long-term CV outcomes in RA are required.

Anti-TNFα therapy may lead to blood pressure reductions through improved endothelium-dependent microvascular function in patients with rheumatoid arthritis

Anti-TNFα therapy may lead to blood pressure reductions through improved endothelium-dependent microvascular function in patients with rheumatoid arthritis