Ovariectomy Reduces Vasocontractile Responses of Rat Middle Cerebral Arteries After Focal Cerebral Ischemia.

ABSTRACT: Effects of sex hormones on stroke outcome are not fully understood. A deleterious consequence of cerebral ischemia is upregulation of vasoconstrictor receptors in cerebral arteries that exacerbate stroke injury. Here, we tested the hypothesis that female sex hormones alter vasocontractile responses after experimental stroke in vivo or after organ culture in vitro, a model of vasocontractile receptor upregulation. Female rats with intact ovaries and ovariectomized (OVX) females treated with 17ß-estradiol, progesterone, or placebo were subjected to transient, unilateral middle cerebral artery occlusion followed by reperfusion (I/R). The maximum contractile response, measured my wire myography, in response to the endothelin B receptor agonist sarafotoxin 6c was increased in female arteries after I/R, but the maximum response was significantly lower in arteries from OVX females. Maximum contraction mediated by the serotonin agonist 5-carboxamidotryptamine was diminished after I/R, with arteries from OVX females showing a greater decrease in maximum contractile response. Contraction elicited by angiotensin II was similar in all arteries. Neither estrogen nor progesterone treatment of OVX females affected I/R-induced changes in endothelin B- and 5-carboxamidotryptamine-induced vasocontraction. These findings suggest that sex hormones do not directly influence vasocontractile alterations that occur after ischemic stroke; however, loss of ovarian function does impact this process.

Self-care Management Intervention in Heart Failure (SMART-HF): A Multicenter Randomized Controlled Trial.

BACKGROUND: Self-care behavior is important in avoiding hospitalization for patients with heart failure (HF) and refers to those activities performed with the intention of improving or restoring health and well-being, as well as treating or preventing disease. The purpose was to study the effects of a home-based mobile device on self-care behavior and hospitalizations in a representative HF-population. METHODS AND RESULTS: SMART-HF is a randomized controlled multicenter clinical trial, where patients were randomized 1:1 to receive standard care (control group [CG]) or intervention with a home-based tool designed to enhance self-care behavior (intervention group [IG]) and followed for 240 days. The tool educates the patient about HF, monitors objective and subjective symptoms and adjusts loop diuretics. The primary outcome is self-care as measured by the European Heart Failure Self-care behavior scale and the secondary outcome is HF related in-hospital days.A total of 124 patients were recruited and 118 were included in the analyses (CG: n = 60, IG: n = 58). The mean age was 79 years, 39% were female, and 45% had an ejection fraction of less than 40%. Self-care was significantly improved in the IG compared to the CG (median (interquartile range) (21.5 [13.25; 28] vs 26 [18; 29.75], p = 0.014). Patients in the IG spent significantly less time in the hospital admitted for HF (2.2 days less, relative risk 0.48, 95% confidence interval 0.32-0.74, P = .001). CONCLUSIONS: The device significantly improved self-care behavior and reduced in-hospital days in a relevant HF population.

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.

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.

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.

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.

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.

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.

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.

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

BACKGROUND: 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. METHODS: 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 (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. RESULTS: ETA 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). CONCLUSION: The 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.

Increased expression of endothelin ET(B) and angiotensin AT(1) 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 microm) 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 ET(A), ET(B), AT(1), and AT(2) 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 ET(B) (by 94%) and AT(1) (by 34%) receptors in the smooth muscle cells of resistance arteries as compared to the control group. There were no significant differences in AT(2) and ET(A) receptor expression between the groups. The results indicate that the expression of arterial smooth muscle ET(B) and AT(1) 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.

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 degrees 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.

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.

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% CI 416-948) in the hypertensive group. Plasma level of NT-proBNP was 90 ng/1 (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.

Reduction of homocysteine in elderly with heart failure improved vascular function and blood pressure control but did not affect inflammatory activity.

We have previously shown that hyperhomocysteinaemia is common in elderly heart failure patients, and is associated with endothelial dysfunction, impaired vasodilatory capacity and a low-grade inflammation. In the present study we examined if supplementation with B6, B12 and folate could normalize the hyperhomocysteinaemia and if so, in turn, would improve the associated parameters. This was an open study without placebo control on heart failure patients with plasma homocysteine > 15 microM. Measurements of cutaneous vascular reactivity, blood pressure, inflammatory activity and endothelial function were performed before and after intervention with intra-individual comparisons. The treatment reduced homocysteine to near normal values and enhanced the hyperaemic response to acetylcholine related to the response to heat. The mean arterial blood pressure and pulse rate was reduced. There was no effect on inflammatory activity, plasma levels of von Willebrand factor, subjective health quality or the hyperaemic responses to sodium nitroprusside or local warming. Hyperhomocysteinaemia in heart failure patients is multifactorial in origin. Folate deficiency, inflammatory activity and reduced renal function could be contributing. It is suggested that supplementation with B-vitamins can improve the vasodilatory capacity and reduce the blood pressure but additional studies are required to confirm this.

Vasodilator effect of endothelin in cutaneous microcirculation of heart failure patients.

The heart failure syndrome is associated with a reduced vasodilatory capacity in cutaneous microvessels. The aim of this study was to investigate the hypothesis that an altered activity of the endothelin system contributes to this reduction. The skin blood flow was recorded by laser Doppler flowmetry in patients with congestive heart failure and in age- and gender-matched controls without clinical signs of heart failure. The vessels were stimulated by iontophoretic administration of endothelin-1. The involvement of the endothelin(A) receptor was studied by co-administration of a specific antagonist; the role of the endothelin(B) receptor was studied by the administration of the selective agonist sarafotoxin 6c. The plasma levels of endothelin-1, C-reactive peptide and N-terminal-pro-Brain Natriuretic Peptide were elevated in heart failure patients. Unexpected, endothelin-1 induced an endothelin(A) mediated vasodilation. In the heart failure group the dilation was reduced to less than half as compared to control. The response to local warming was reduced in parallel indicating that the attenuation of the response in the heart failure group can be explained by the general decline in vascular reactivity. The response to endothelin(B) receptor stimulation did not differ between the groups. The reduction in endothelin-1 responsiveness is paralleled by a general reduction in microvascular vasodilatory capacity, a phenomenon of increased vascular stiffness in the of heart failure subjects.