Marie-Louise Edvinsson

Cutaneous vascular reactivity is reduced in aging and in heart failure: association with inflammation

In the present study, we have investigated whether changes in vascular reactivity in congestive heart failure (CHF) patients can be detected in the cutaneous microvessels and whether these changes are due to endothelial dysfunction, are affected by increasing age and related to an ongoing inflammation. The responses to local warming and iontophoretically administered endothelium-dependent and -independent vasodilators were investigated in healthy young adults, healthy elderly adults and elderly adults with CHF. The results were correlated with plasma concentrations of vascular risk factors and markers for endothelial dysfunction and inflammation. The vasorelaxant responses were reduced in the elderly groups and were attenuated further in the CHF group. This group also had increases in levels of several markers associated with inflammation, higher blood glucose and homocysteine levels, a lower low-density lipoprotein-cholesterol and a rise in the concentration of von Willebrand factor, indicating a prothrombotic endothelial function. The severity of the heart failure, measured as the plasma level of brain natriuretic peptide, correlated with the intensity of inflammation and to the changes in vascular risk factors and endothelial function. It is concluded that the reactivity of the cutaneous microvessels is reduced with age, and the presence of CHF causes a further impairment. There is endothelial dysfunction in CHF, but it is uncertain to what extent this contributes to the reduced vasodilatory capacity. The inflammatory response appears central for many of the manifestations of the CHF syndrome.

Cigarette smoking leads to reduced relaxant responses of the cutaneous microcirculation

Background Smoking is a major risk factor for cardiovascular disease. The present study was undertaken to examine if cigarette smoking translates into reduced relaxant responses of the peripheral microcirculation. Methods The cutaneous forearm blood flow was measured by laser Doppler flowmetry. The vasodilator response to the iontophorectic administration of acetylcholine (ACh), acting via an endothelial mechanism, and sodium nitroprusside (SNP), and acting via a smooth muscle mechanism were studied. The study population consisted of 17 nonsmokers and 17 current smokers (mean age 64 ± 2 years, 13 females and 4 males) in each matched group. Results There was no difference between the groups in baseline characteristics or in basal flow. Smokers showed however significantly reduced responses to both ACh (mean ± SEM, from 973 ± 137% in nonsmokers to 651 ± 114% in smokers, p < 0.05) and SNP (from 575 ± 111% in nonsmokers to 355 ± 83% in smokers, p < 0.05). The response to the local heating (44 °C) was reduced in smokers (from 1188 ± 215% in nonsmokers to 714 ± 107% in smokers, p < 0.01). In addition, there was no difference between men and women within the groups. Conclusions The data show that cigarette smoking results in reduced peripheral microvascular responses to both endothelial and smooth muscle cell stimulation in healthy subjects, suggesting a generalized microvascular vasomotor function.

Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease.

BackgroundEndothelin-1 and angiotensin II are strong vasoconstrictors. Patients with ischemic heart disease have elevated plasma levels of endothelin-1 and angiotensin II and show increased vascular tone. The aim of the present study was to examine the endothelin and angiotensin II receptor expression in subcutaneous arteries from patients with different degrees of ischemic heart disease.MethodsSubcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ETA) and type B (ETB), and angiotensin type 1 (AT1) and type 2 (AT2) receptors expression and function were examined using immunohistochemistry, Western blot and in vitro pharmacology.ResultsETA and, to a lesser extent, ETB receptor staining was observed in the healthy vascular smooth muscle cells. The level of ETB receptor expression was higher in patients undergoing CABG surgery (250% ± 23%; P < 0.05) and in the patients with angina pectoris (199% ± 6%; P < 0.05), than in the healthy controls (100% ± 28%). The data was confirmed by Western blotting. Arteries from CABG patients showed increased vasoconstriction upon administration of the selective ETB receptor agonist sarafotoxin S6c, compared to healthy controls (P < 0.05). No such difference was found for the ETA receptors. AT1 and, to a lesser extent, AT2 receptor immunostaining was seen in the vascular smooth muscle cells. The level of AT1 receptor expression was higher in both the angina pectoris (128% ± 25%; P < 0.05) and in the CABG patients (203% ± 41%; P < 0.05), as compared to the healthy controls (100% ± 25%). The increased AT1 receptor expression was confirmed by Western blotting. Myograph experiment did however not show any change in vasoconstriction to angiotensin II in CABG patients compared to healthy controls (P = n.s).ConclusionThe results demonstrate, for the first time, upregulation of ETB and AT1 receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions.

Reduced responsiveness of cutaneous microcirculation in essential hypertension – A pilot study

Objective. Our hypothesis states that the reactivity of the cutaneous microcirculation is reduced in patients with hypertension compared with healthy subjects. The objective was to verify the hypothesis by measuring microvascular function in hypertensive patients. Design. The study was a controlled trial with two arms: 15 hypertensives and 15 normotensives were enrolled, aged 30–60 years, and in hypertensives, a diastolic blood pressure of >90 mmHg. The hypertensive patients were compared with gender‐ and age‐matched controls having a diastolic blood pressure <90 mmHg. The patients were kept on their medication. Method. The local cutaneous forearm blood flow was measured by Laser‐Doppler flowmetry. The blood flow response to local warming (44°C), to the endothelium‐dependent vasodilator acetylcholine (ACh), or to the endothelium‐independent dilators sodium nitroprusside (SNP) and calcitonin gene‐related peptide (CGRP) administered by iontophoresis were determined. Inflammatory markers and NT‐pro brain natriuretic peptide (NT‐proBNP) levels in plasma was also measured. Electrocardiograms (ECG) were evaluated and the subjects answered a lifestyle questionnaire. Results. The percentage change in vasodilator response to CGRP was significantly lower in the hypertensives compared with normotensives, 285% (95% CI 86–484) vs 764% (95% CI 366–1162) of baseline, p<0.05. The change to local warming was 2191% (95% CI 1574–2807) in normotensives vs 1384% (95% CI 852–1917) in the hypertensives, p<0.05. The vasodilator response to ACh was 1249% (95% CI 895–1602) in the normotensives and 873% (95% CI 610–1136) in the hypertensives. The vasodilator response to SNP in the normotensives was 771% (95% CI 436–1107) and 682% (95% CI 416–948) in the hypertensive group. Plasma level of NT‐proBNP was 90 ng/l (95% CI 35–145) in normotensives vs 285 ng/l (95% CI 70–499) in hypertensives (p = 0.06). The ECGs showed a tendency towards left ventricular hypertrophy (LVH) in hypertensives. Conclusion. Patients with essential hypertension had significantly reduced microvascular dilator responses to CGRP and to local warming. Also, there was a tendency towards reduced responses to ACh. This points towards a generally weaker responsiveness of the cutaneous microvessels in hypertensives and could be a contributing factor to the development of high blood pressure. Patients with essential hypertension also had a tendency of higher plasma levels of NT‐proBNP, which could be seen as an early sign of organ damage.

Effect of medication on microvascular vasodilatation in patients with systemic lupus erythematosus.

The aim of this study was to investigate the microvascular responses in the skin, to local heat, iontophoretically administered acetylcholine and to sodium nitroprusside in relation to cardiovascular damage in patients with systemic lupus erythematosus (SLE) and matched controls. We also wanted to examine if the ongoing medication in SLE patients influenced this vascular response. We investigated 30 women with SLE and compared them with 20 age and sex-matched controls. The cutaneous blood flow response to local heat (+44°C), iontophoretically administered endothelium-dependent (acetylcholine), as well as independent (sodium nitroprusside) vasodilatation, was measured by laser Doppler flowmetry. Clinical data and medication were retrieved from the clinical database and patient records. The cutaneous microvascular reactivity did not differ between SLE patients and a group of matched controls nor did it correlate with cardiovascular damage [assessed by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI)]. However, patients on antimalarial drugs (hydroxychloroquine n = 8 and chloroquine diphosphate n = 3) responded more strongly to sodium nitroprusside (endothelium-independent vasodilatation) compared with those without antimalarial drugs (p < 0.01). The response to acetylcholine was higher among patients on warfarin compared with those without (p < 0.05), whereas glucocorticoid use (≥5 mg daily) was associated with reduced response to acetylcholine (p < 0.05). Smokers in general tended to have a lower response to acetylcholine (p = 0.064). Smoking SLE patients versus non-smoking SLE patients had a significantly lower response to acetylcholine (p = 0.01). Medication with antimalarial drugs-enhanced endothelium-independent vasodilatation, while glucocorticoid use was associated with reduction and warfarin-treatment with enhancement of endothelium-dependent vasodilatation. Therefore, despite there is no difference in microvascular endothelium-dependent vasodilatation, other factors such as medication and smoking may affect vasodilatation in SLE patients.

Deteriorated function of cutaneous microcirculation in chronic congestive heart failure

Background Chronic congestive heart failure is a complex condition that leads to dysfunction in the peripheral microcirculation. We have previously shown that vascular reactivity is reduced with increasing age. In this study, we examined a group of very old patients with severe chronic heart failure to test the hypothesis that vascular function is further compromised by a combination of heart failure and aging. Methods Cutaneous forearm blood flow was measured by laser Doppler flowmetry and compared among three groups: Group 1 (n = 20, mean ± SE: 85.5 ± 4 years), heart failure patients with New York Heart Association class IV (NYHA IV) and with a NT-proBNP level ≥ 5000 ng/L; Group 2 (n = 15, mean ± SE: 76.5 ± 2 years), heart failure patients with NYHA II and NT-proBNP ≤ 2000 ng/L, and Group 3 (n = 10, mean ± SE: 67.6 ± 3.0 years), healthy controls with no clinical signs of heart failure. The vasodilator response to the iontophoretic administration of acetylcholine (ACh), acting via an endothelial mechanism, and sodium nitroprusside (SNP), acting via a smooth muscle cell mechanism, were studied. Results All patients with heart failure had significantly reduced vascular reactivity independent of the mode of stimulation (ACh, SNP or heat) when compared to healthy controls. However, the responses did not differ between the two groups of heart failure patients. Conclusions Cutaneous vascular reactivity is reduced in heart failure patients and does not correlate with the severity of the condition or age of patients.

Increased expression of endothelin ETB and angiotensin AT1 receptors in peripheral resistance arteries of patients with suspected acute coronary syndrome

Patients who experience chest pain, in which ischemic heart disease has been ruled out, still have an increased risk of future ischemic cardiac events and premature death, possibly due to subclinical endothelial dysfunction. A feature of endothelial dysfunction is an increased expression of arterial vasoconstrictor endothelin (ET) and angiotensin (AT) receptors. Our aim was to investigate if the arterial expressions of these receptors are changed in patients with suspected but ruled out acute coronary syndrome (ACS). Small subcutaneous arteries (diameter of 100 µm) were surgically removed in an abdominal biopsy from 12 patients suspicious of ACS (susp ACS), admitted to the medical telemetry unit for chest pain. The vessels were analyzed for their receptor protein expression by quantitative immunohistochemistry using specific antibodies directed against ETA, ETB, AT1, and AT2 receptors. The control group (controls) consisted of eight healthy volunteers matched for age and sex with no previous cardiac illness or medication. The susp ACS group had an increased expression of ETB (by 94%) and AT1 (by 34%) receptors in the smooth muscle cells of resistance arteries as compared to the control group. There were no significant differences in AT2 and ETA receptor expression between the groups. The results indicate that the expression of arterial smooth muscle ETB and AT1 receptors are increased in patients with suspected but ruled out ACS. These receptor changes could be important in the regulation of coronary tone and in the development of atherosclerosis, and may be related to increased cardiovascular risk.

Reduced peripheral vascular reactivity in refractory angina pectoris: Effect of enhanced external counterpulsation

Aims To examine if the skin microvascular bed is altered and can be modified by enhanced external counterpulsation (EECP) in patients with chronic refractory angina. Methods Twenty patients diagnosed with refractory angina were divided into EECP (n = 10) or no EECP (n = 10) groups. The data were compared to matched healthy subjects (n = 20). The cutaneous forearm microvascular blood flow was measured by Laser-Doppler flowmetry. The vascular responsiveness to iontophoretic administration of acetylcholine (ACh), sodium nitroprusside (SNP) and local skin warming were studied. Measurements of Canadian Cardiovascular Society (CCS)-class, blood pressure and plasma samples were registered. Results EECP patients showed reduced CCS-class compared to no EECP (P < 0.05). Both EECP and no EECP (P < 0.05) groups had decreased systolic blood pressure (SBP) as compared to SBP at baseline (P < 0.05). There was no difference in resting blood flow between the two refractory groups at baseline as well as after EECP and seven weeks of follow-up. Responses to heating, the responses to ACh and SNP in the cutaneous microcirculation were lower in both groups of refractory angina patients as compared to healthy subjects (P < 0.05). EECP patients corresponded positively to the treatment shown by reduced plasma level of soluble interleukin-2 receptor and CCS-class. Conclusions Refractory angina patients have reduced responsiveness in their cutaneous microcirculation to ACh, SNP and heat compared to healthy subjects. Although EECP reduced the CCS-class, this effect was not associated with improvements in responsiveness of the cutaneous microcirculation.

Brain natriuretic peptide is a potent vasodilator in aged human microcirculation and shows a blunted response in heart failure patients.

Background Brain natriuretic peptide (BNP) is normally present in low levels in the circulation, but it is elevated in parallel with the degree of congestion in heart failure subjects (CHF). BNP has natriuretic effects and is a potent vasodilator. It is suggested that BNP could be a therapeutic alternative in CHF. However, we postulated that the high levels of circulating BNP in CHF may downregulate the response of microvascular natriuretic receptors. This was tested by comparing 15 CHF patients (BNP > 3000 ng/L) with 10 matched, healthy controls. Methods Cutaneous microvascular blood flow in the forearm was measured by laser Doppler Flowmetry. Local heating (+44°C, 10 min) was used to evoke a maximum local dilator response. Results Non-invasive iontophoretic administration of either BNP or acetylcholine (ACh), a known endothelium-dependent dilator, elicited an increase in local flow. The nitric oxide synthase inhibitor, l-N-Arginine- methyl-ester (L-NAME), blocked the BNP response (in controls). Interestingly, responses to BNP in CHF patients were reduced to about one third of those seen in healthy controls (increase in flow: 251% in CHF vs. 908% in controls; P < 0.001). In contrast, the vasodilator responses to ACh and to local heating were only somewhat attenuated in CHF patients. Thus, dilator capacity and nitric oxide signalling were not affected to the same extent as BNP-mediated dilation, indicating a specific downregulation of the latter response. Conclusions The findings show for the first time that microvascular responses to BNP are markedly reduced in CHF patients. This is consistent with the hypothesis of BNP receptor function is downregulated in CHF.

Characterization of Relaxant Responses to Natriuretic Peptides in the Human Microcirculation In Vitro and In Vivo

We characterized the vasodilatory effects of ANP, BNP, and CNP in human subcutaneous arterioles in vitro and the cutaneous microcirculation in vivo.