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

<p>Abstract</p> <p>Background</p> <p>Endothelin-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.</p> <p>Methods</p> <p>Subcutaneous 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 (ET_A) and type B (ET_B), and angiotensin type 1 (AT₁) and type 2 (AT₂) receptors expression and function were examined using immunohistochemistry, Western blot and <it>in vitro </it>pharmacology.</p> <p>Results</p> <p>ET_Aand, to a lesser extent, ET_Breceptor staining was observed in the healthy vascular smooth muscle cells. The level of ET_Breceptor 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 ET_Breceptor agonist sarafotoxin S6c, compared to healthy controls (P < 0.05). No such difference was found for the ET_Areceptors. AT₁and, to a lesser extent, AT₂receptor immunostaining was seen in the vascular smooth muscle cells. The level of AT₁receptor 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 AT₁receptor 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).</p> <p>Conclusion</p> <p>The results demonstrate, for the first time, upregulation of ET_Band AT₁receptors 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.</p

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 degrees 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% Cl 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

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

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

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

Objective: We characterized the vasodilatory effects of ANP, BNP, and CNP in human subcutaneous arterioles in vitro and the cutaneous microcirculation in vivo. Methods: The in vitro experiments were performed using wire myography and the responses were characterized by the use of inhibitors for nitric oxide (L-NAME), prostaglandin synthesis (indomethacin), or the endothelium-derived hyperpolarization factor. In vivo, the vasorelaxant effect of iontophoretically administrated BNP or CNP was measured with a noninvasive laser Doppler technique. Involvement of nitric oxide or prostaglandins was assessed by L-NAME or indomethacin given by iontophoresis. Results: In vitro all three peptides showed significant vasodilatation with the efficacy order: CNP > BNP = ANP. The BNP-induced vasodilatation, but not that of ANP or CNP, was significantly reduced by pretreatment with indomethacin or L-NAME. In vivo administration of BNP induced a marked vasodilatory response that was attenuated by local pretreatment of L-NAME. Indomethacin by itself resulted in increased cutaneous perfusion. Conclusions: NPs are potent vasodilators in the human subcutaneous circulation. The response to BNP differs from that of the other peptides as it seems dependent on cyclooxygenase products and nitric oxide

High NT-proBNP Is a Strong Predictor of Outcome in Elderly Heart Failure Patients.

All patients older than 65 years (184 men; mean age, 78+/-0.8 years/181 women; mean age, 82+/-0.6 years) seeking medical attention at the Lund University Hospital Emergency Clinic during a 2-year period who had an N-terminal prohormone brain natriuretic peptide (NT-proBNP) value >2000 pg/mL were followed up for survival. Mortality in the entire population was 21% after 3 months, 35% after 1 year, and 40% after 2 years. Multivariate analysis indicated that the NT-proBNP level and the New York Heart Association (NYHA) functional class were stronger predictors of mortality than were echocardiographic estimation of left ventricular ejection fraction or chest radiography. Patients who survived the first year were younger, had higher systolic blood pressure, had lower plasma creatinine, had lower inflammatory activity, and were treated with lower doses of furosemide. The results indicate that in this population, NT-proBNP level together with assessment of NYHA class gives the best prognostic information of 1-year mortality. (Am J Geriatr Cardiol. 2008;17:13-20)

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

Improved outcome with standardized plan for clinical management of acute decompensated chronic heart failure

Background Our overall goal is to improve clinical care for inpatients with chronic heart failure (CHF). A retrospective assessment of CHF patients admitted to our hospital over the past decade (2005 vs. 2014) indicated a need for better strategies to evaluate clinical treatment, implement best practices and achieve optimal patient outcome. To that purpose, we developed a standardized plan to improve in-hospital treatment of acute decompensated CHF patients. Methods & Results Retrospective chart reviews were conducted to compare three cohorts of CHF patients admitted to the University Hospital of Lund at different time points over a 12-year period: 2005 (365 patients), 2014 (172 patients) and 2017–2018 (57 patients). Little improvement was seen between 2005 and 2014 with respect to one-year mortality (35% vs. 34%) and adequate treatment with recommended medications, e.g., use of renin-angiotensin system blockers (45% vs. 51%). A standardized treatment plan was devised to improve outcomes. A third cohort, treated under the plan (2017–2018), was compared with the 2014 cohort. One-year mortality (18% vs. 34%) and 30-day readmission (5% vs. 30%) were dramatically decreased, and adherence to medication guidelines was achieved. Key elements of the plan included well-defined treatment procedures, enhanced communication and teamwork, education, adequate time for treatment (5 days) and post-discharge follow-up as necessary. Natriuretic peptide (NT-proBNP) levels were useful for assessing patient status, prognosis and response to treatment. Conclusion Development of a standard plan for clinical management of acute decompensated CHF patients resulted in significant improvements in patient outcome, as reflected in decreased rates of 30-day readmission and one-year mortality

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 degrees 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 = 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

Secondhand cigarette smoke induces increased expression of contractile endothelin receptors in rat coronary arteries via a MEK1/2 sensitive mechanism

Objectives: Cigarette smoke, a strong risk factor for cardiovascular diseases, upregulates contractile endothelin (ET) receptors in coronary arteries. The present study examined the effects of second hand cigarette smoke exposure on the contractile endothelin receptors and the role of the MEK1/2 pathway in rat coronary arteries. Design: Rats were exposed to secondhand smoke (SHS) for 8 weeks followed by intraperitoneal injection of a MEK1/2 inhibitor, U0126 daily for another 4 weeks. Contractile responses of isolated coronary arteries were recorded by a sensitive wire myograph. The receptor protein expression levels were examined by Western blotting. Results: The results showed that SHS in vivo caused increased expression of ET receptors ETA and ETB, and that the MEK1/2 blocker U0126 significantly reversed SHS exposure-increased ETA-mediated contractile responses and protein levels. Similar alterations were observed in ETB receptors. U0126 showed dose-dependent effects on SHS-induced response on contractile property and protein levels of the ETB receptor. However, only the higher dose U0126 (15 mg/kg) had inhibitory effects on the ETA receptor. Conclusions: Taken together, our data show that SHS increases contractile ET receptors and MEK1/2 pathway inhibitor offsets SHS exposure-induced ETA and ETB receptor upregulation in rat coronary arteries