Distribution of Ixodes ricinus ticks and prevalence of tick-borne encephalitis virus among questing ticks in the Arctic Circle region of northern Norway.

This study investigated the geographical distribution of Ixodes ricinus and prevalence of the tick-borne encephalitis virus (TBEV) in northern Norway. Flagging for questing I. ricinus ticks was performed in areas ranging from Vikna in Nord-Trøndelag County, located 190km south of the Arctic Circle (66.3°N), to Steigen in Nordland County, located 155km north of the Arctic Circle. We found that ticks were abundant in both Vikna (64.5°N) and Brønnøy (65.1°N). Only a few ticks were found at locations ∼66°N, and no ticks were found at several locations up to 67.5°N. Real-time PCR (RT-PCR) analyses of the collected ticks (nymphs and adults) for the presence of TBEV revealed a low prevalence (0.1%) of TBEV among the nymphs collected in Vikna, while a prevalence of 0% to 3% was found among nymphs collected at five locations in Brønnøy. Adult ticks collected in Vikna and Brønnøy had higher rates of TBEV infection (8.6% and 0%-9.0%, respectively) than the nymphs. No evidence of TBEV was found in the few ticks collected further north of Brønnøy. This is the first report of TBEV being detected at locations up to 65.1°N. It remains to be verified whether viable populations of I. ricinus exist at locations north of 66°N. Future studies are warranted to increase our knowledge concerning tick distribution, tick abundance, and tick-borne pathogens in northern Norway.

Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study.

In a randomized, open-label trial, de novo heart transplant recipients were randomized to everolimus (3-6 ng/mL) with reduced-exposure calcineurin inhibitor (CNI; cyclosporine) to weeks 7-11 after transplant, followed by increased everolimus exposure (target 6-10 ng/mL) with cyclosporine withdrawal or standard-exposure cyclosporine. All patients received mycophenolate mofetil and corticosteroids. A total of 110 of 115 patients completed the 12-month study, and 102 attended a follow-up visit at month 36. Mean measured GFR (mGFR) at month 36 was 77.4 mL/min (standard deviation [SD] 20.2 mL/min) versus 59.2 mL/min (SD 17.4 mL/min) in the everolimus and CNI groups, respectively, a difference of 18.3 mL/min (95% CI 11.1-25.6 mL/min; p < 0.001) in the intention to treat population. Multivariate analysis showed treatment to be an independent determinant of mGFR at month 36. Coronary intravascular ultrasound at 36 months revealed significantly reduced progression of allograft vasculopathy in the everolimus group compared with the CNI group. Biopsy-proven acute rejection grade ≥2R occurred in 10.2% and 5.9% of everolimus- and CNI-treated patients, respectively, during months 12-36. Serious adverse events occurred in 37.3% and 19.6% of everolimus- and CNI-treated patients, respectively (p = 0.078). These results suggest that early CNI withdrawal after heart transplantation supported by everolimus, mycophenolic acid and steroids with lymphocyte-depleting induction is safe at intermediate follow-up. This regimen, used selectively, may offer adequate immunosuppressive potency with a sustained renal advantage.

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial.

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12-month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7-11 weeks after HTx or standard cyclosporine immunosuppression. Ninety-five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm(3) and 13.8 ± 28.0 mm(3) [all p-values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor-1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus-based CNI-free can potentially be considered in suitable de novo HTx recipients.

Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial.

In a randomized, open-label trial, everolimus was compared to cyclosporine in 115 de novo heart transplant recipients. Patients were assigned within 5 days posttransplant to low-exposure everolimus (3­6 ng/mL) with reduced-exposure cyclosporine (n = 56), or standard-exposure cyclosporine (n = 59), with both mycophenolate mofetil and corticosteroids. In the everolimus group, cyclosporine was withdrawn after 7­11 weeks and everolimus exposure increased (6­10 ng/mL). The primary efficacy end point, measured GFR at 12 months posttransplant, was significantly higher with everolimus versus cyclosporine (mean ± SD: 79.8 ± 17.7 mL/min/1.73 m2 vs. 61.5 ± 19.6 mL/min/1.73 m2; p < 0.001). Coronary intravascular ultrasound showed that the mean increase in maximal intimal thickness was smaller (0.03 mm [95% CI 0.01, 0.05 mm] vs. 0.08 mm [95% CI 0.05, 0.12 mm], p = 0.03), and the incidence of cardiac allograft vasculopathy (CAV) was lower (50.0% vs. 64.6%, p = 0.003), with everolimus versus cyclosporine at month 12. Biopsy-proven acute rejection after weeks 7­11 was more frequent with everolimus (p = 0.03). Left ventricular function was not inferior with everolimus versus cyclosporine. Cytomegalovirus infection was less common with everolimus (5.4% vs. 30.5%, p < 0.001); the incidence of bacterial infection was similar. In conclusion, everolimus-based immunosuppression with early elimination of cyclosporine markedly improved renal function after heart transplantation. Since postoperative safety was not jeopardized and development of CAV was attenuated, this strategy may benefit long-term outcome.

Systemic markers of inflammation are associated with cardiac allograft vasculopathy and an increased intimal inflammatory component.

We evaluated an extensive profile of clinical variables and immune markers to assess the inflammatory milieu associated with cardiac allograft vasculopathy (CAV) assessed by intravascular ultrasound (IVUS) and virtual histology (VH). In total, 101 heart transplant (HTx) recipients were included and underwent IVUS/VH examination and measurement of plasma C-reactive protein (CRP), soluble tumor necrosis factor receptor-1, interleukin-6, osteoprotegerin, soluble gp130, von Willebrand factor, vascular cell adhesion molecule-1 (VCAM-1) and neopterin. Mean Maximal Intimal Thickness (MIT) was 0.61 +/- 0.19 mm and mean fibrotic, fibrofatty, dense calcified and necrotic core components were 55 +/- 15, 14 +/- 10, 15 +/- 13 and 17 +/- 9%, respectively. In multivariate analysis, CRP > 1.5 mg/L (OR 4.6, p < 0.01), VCAM-1 > 391 ng/mL (adjusted OR 3.2, p = 0.04) and neopterin > 7.7 nmol/L (OR 3.8, p = 0.02) were independently associated with MIT > 0.5 mm. Similarly, CRP > 1.5 mg/L (OR 3.7, p < 0.01) and VCAM-1 > 391 (OR 2.7, p = 0.04) were independently associated with an increased intimal inflammatory component (dense calcified/necrotic core component > 30%). Advanced CAV is associated with elevated CRP, VCAM-1 and neopterin and the two former biomarkers are also associated with an increased intimal inflammatory component. Forthcoming studies should clarify if routine measurements of these markers can accurately identify HTx recipients at risk of developing advanced CAV and vulnerable lesions.

Treatment-related differences in cardiovascular risk factors in long-term survivors of testicular cancer.

OBJECTIVE: Treatment in testicular cancer survivors (TCSs) may be followed by cardiovascular disorders. We have examined whether today's three treatment modalities are associated with a biochemical cardiovascular risk profile. MATERIALS AND METHODS: In this cross sectional study serum inflammatory markers, atherogenic lipoproteins and gonadal hormones were measured in 589 orchiectomized TCSs who have been treated 5-20 years previously. There were 140 patients treated by surgery alone (SURG), 231 who had had infradiaphragmatic radiotherapy alone (RAD), and 218 who had chemotherapy with or without additional surgery (CHEM). RESULTS: (1) The RAD group had higher levels of high-sensitivity C-reactive protein and soluble CD40 ligand compared to the SURG group. (2) The CHEM group had lower levels of high density lipoprotein cholesterol and an increased apolipoprotein B/apolipoprotein A-1 ratio than the SURG group. The prevalence of metabolic syndrome was higher in the CHEM group than in the SURG group. (3) Hypogonadism was significantly more prevalent in the CHEM than in the SURG group. CONCLUSION: Treatment for TC was related to long-term biochemical cardiovascular risk factors by different pathways: Radiation treatment is followed by elevated serum markers of chronic inflammation and endothelial dysfunction, whereas chemotherapy is followed by the development of atherogenic lipid changes and of the metabolic syndrome. This study provides justification for a prospective study of the impact of these treatment modalities on cardiovascular risk in testicular cancer survivors. In the interim testicular cancer survivors should monitor cardiovascular risk over time.

Clopidogrel increases expression of chemokines in peripheral blood mononuclear cells in patients with coronary artery disease: results of a double-blind placebo-controlled study.

BACKGROUND: Chemokines and platelet activation are both important in atherogenesis. Platelet inhibitors are widely used in coronary artery disease (CAD), and we hypothesized that the platelet inhibitor clopidogrel could modify chemokines in CAD patients. OBJECTIVES: We sought to investigate the effect of clopidogrel on the expression of chemokines and chemokine receptors in peripheral blood mononuclear cells (PBMC) in CAD patients. PATIENTS/METHODS: Thirty-seven patients with stable angina were randomized to clopidogrel (n = 18) or placebo (n = 19). PBMC, blood platelets and plasma were collected at baseline and after 7-10 days in the patients, and in 10 healthy controls. mRNA levels of chemokines and chemokine receptors in PBMC were analyzed by ribonuclease protection assays and real-time reverse transcriptase polymerase chain reaction. Platelet activation was studied by flow cytometry. RESULTS: (i) At baseline, the gene expression of the regulated on activation normally T-cell expressed and secreted (RANTES) chemokines and macrophage inflammatory peptide (MIP)-1beta in PBMC, the expression of CD62P and CD63 on platelets and the levels of platelet-derived microparticles (PMP) were elevated in angina patients comparing healthy controls; (ii) markers of platelet activation were either reduced (CD63) or unchanged (CD62P, PMP, beta-thromboglobulin) during clopidogrel therapy; (iii) in contrast, clopidogrel significantly up-regulated the gene expression of RANTES and MIP-1beta in PBMC, while no changes were found in the placebo group; (iv) a stable adenosine 5'-diphosphate metabolite attenuated the release of MIP-1beta, but not of RANTES, from activated PBMC in vitro. CONCLUSIONS: Even if we do not argue against a beneficial role for clopidogrel in CAD, our findings may suggest potential inflammatory effects of clopidogrel in CAD.

Serial measurements of peripheral vascular reactivity and exercise capacity in congestive heart failure and after heart transplantation.

BACKGROUND: The regulation of nutritive blood flow to skeletal muscles during exercise seems to make an important contribution to exercise capacity. In congestive heart failure (CHF) this regulation seems to be impaired, with attenuated peripheral vasodilatory capacity. The results regarding improvement of peripheral vasoreactivity after heart transplantation (HTx) are conflicting, and the contribution of impaired peripheral vasoreactivity to the observed reduced exercise capacity among heart transplant recipients (HTR) has not been well elucidated. We therefore assessed the reversibility of impaired vasoreactivity in forearm and calf after HTx with relationship to exercise capacity. METHODS AND RESULTS: The vasoreactivity of both forearm and calf was studied with venous occlusion plethysmography and related to exercise capacity in 64 patients with CHF and in 22 controls. Of these patients, 29 patients underwent HTx, and the same measurements were performed 10 days, 6 months and 1 year after HTx, and in a group of 15 HTR who had undergone HTx several years ago. Our main findings were (1) impaired resting blood flow in patients with CHF improved after HTx and even surpassed levels of controls; (2) peak forearm blood flow remained attenuated early after HTx, but normalized during the first year postoperatively; (3) both forearm and calf minimal resistance remained elevated after HTx; (4) vascular reactivity displays regional variations in forearm and calf both during CHF and after HTx; and (5) peripheral vascular reactivity relate to exercise performance in both patients with CHF and HTR, but the relationship seemed more pronounced in CHF. CONCLUSION: With impaired vasoreactivity related to limited exercise capacity in CHF, improvement is evident after HTx, but both forearm and calf minimal resistance remains elevated. These findings suggest increased vasoconstrictor drive to both exercising and non-exercising muscles, possibly contributing to persistent physical limitation after HTx.

[Angioplasty in acute myocardial infarction in patients transferred from other hospitals]. / Angioplastikk ved akutt hjerteinfarkt hos pasienter overført fra annet sykehus.

BACKGROUND: Primary or rescue angioplasty are reperfusion modalities in selected patients with acute myocardial infarction, after initial diagnosis in local hospitals. We sought to evaluate the feasibility and safety of transporting patients to a tertiary care hospital for interventional treatment. MATERIALS AND METHODS: Between January 1999 and April 2000, 50 consecutive patients were included in this prospective observational study. Comparisons were performed between patients admitted to primary angioplasty, either directly (n = 20; group A) or from other hospitals (n = 14; group B), and those transferred for rescue angioplasty (n = 16; group C). RESULTS: No severe complications occurred during interhospital transport. Median time interval from onset of symptoms to hospitalization was comparable between groups. Median time interval from onset of symptoms to balloon inflation in group C (340 minutes) was significantly longer than in groups A and B (181 and 130 minutes). All patients were alive at follow-up after median 230 days. Median echocardiographically determined left ventricular ejection fraction in group A was non-significantly higher (50%) than in groups B and C (43% and 46%). INTERPRETATION: Acute transfer for primary or rescue angioplasty is feasible and safe for selected patients with acute myocardial infarction.

Omega-3 fatty acids enhance tumor necrosis factor-alpha levels in heart transplant recipients.

BACKGROUND: Proinflammatory cytokines may contribute to clinical complications in heart transplant (HTx) recipients. Previous studies have shown immunomodulating effects of omega-3 fatty acids, but the results are somewhat conflicting. In this study, we examined plasma levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 10, and their relations to antioxidant vitamins in 45 HTx recipients before and after treatment with omega-3 fatty acids or placebo. METHODS: The patients were long-time survivors of heart transplantation, randomized in a double-blind fashion to receive omega-3 fatty acids (3.4 g/day) or placebo for 1 year. Plasma levels of cytokines were measured by enzyme immunoassays and vitamin A, vitamin E, and beta-carotene by high-performance liquid chromatography. RESULTS: In the omega-3, but not in the placebo group, there was a rise in the proinflammatory cytokine TNF-alpha (P<0.05), a decrease in the anti-inflammatory cytokine IL-10 (P=0.07), and a rise in TNF/IL-10 ratio (P<0.05) after 12 months, suggesting a proinflammatory net effect. In the omega-3 group, the increase in TNF-alpha was associated with an increase in eicosapentaenoic acid in plasma (r=0.58, P<0.02). During omega-3 fatty-acid treatment, but not during placebo, there was a decrease in vitamin E (P<0.05) and beta-carotene (P<0.05) levels, and the decrease in vitamin E was inversely correlated with the increase in TNF-alpha (r= -0.56, P<0.01). The rise in TNF-alpha levels during omega-3 fatty acids treatment was most pronounced in those patients with transplant coronary artery disease (P<0.04). CONCLUSION: Our data suggest that omega-3 fatty acids in HTx recipients may change the balance between proinflammatory and anti-inflammatory cytokines in an inflammatory direction, possibly related to prooxidative effects of these fatty acids.

[Immunomodulating treatment in advanced heart failure--effect of intravenous immunoglobulin]. / Immunmodulerende behandling ved avansert hjertesvikt--effekt av intravenøs immunglobulin.

BACKGROUND: Congestive heart failure is characterised by enhanced immune activation. Immune-mediated mechanisms may play a pathogenic role, hence the growing interest in therapeutic regimens that could modulate the immune response in heart failure. MATERIAL AND METHODS: In the present report we discuss the pathogenic role of immunological and inflammatory mediators in the pathophysiology of heart failure and discuss different treatment modalities with focus on our recent study with intravenous immunoglobulin. In that study 40 patients with symptomatic chronic heart failure and left ventricular ejection fraction (LVEF) < 40% were randomised in a double-blind fashion to receive therapy with immunoglobulin or placebo for a total period of 26 weeks. RESULTS: We found that intravenous immunoglobulin, but not placebo, shifted the cytokine balance in an anti-inflammatory direction, and that such a shift was associated with improvement in LVEF by 5 EF units. Functional capacity and haemodynamic variables also improved. INTERPRETATION: Our study supports the hypothesis that immunological variables might be of significant importance in the pathogenesis of heart failure and it suggests a potential for immunomodulating therapy in addition to optimal conventional cardiovascular treatment regimens in such patients. These issues are further discussed in the present article.

[Inhalation of a prostacyclin analog (iloprost) in primary and secondary pulmonary hypertension]. / Inhalasjon av en prostasyklinanalog (iloprost) ved primaer og sekundaer pulmonal hypertensjon.

BACKGROUND: Vasodilative therapy in the form of calcium channel blockers and, recently, continuous intravenous prostacyclin has improved exercise capacity and reduced mortality in primary pulmonary hypertension. Their clinical value is limited by either low rate of response or serious side effects. These shortcomings could be overcome by the use of iloprost, a stable prostacyclin analogue. Administering it by inhalation, we assessed its short-term efficacy in patients with primary and secondary pulmonary hypertension. MATERIAL AND METHODS: We studied six patients with primary and six with secondary pulmonary hypertension, all with New York Heart Association functional class III or IV symptoms of congestive heart failure. Iloprost was nebulised with 8 l/min of oxygen and administered in increasing doses from 10 to 40 micrograms via a facemask. The haemodynamic effects of iloprost was assessed by right-heart catheterisation. RESULTS: Inhalation of iloprost was well tolerated, and produced a median reduction in mean pulmonary artery pressure from 52 (42-63) to 41 (35-56) mm Hg (p < 0.05). Cardiac output increased from 3.5 (2.8-4.3) to 4.1 (3.1-5.1) l/min (p < 0.05) and pulmonary vascular resistance decreased from 1036 (722-1526) to 753 (446-1107) dyn.sek.cm-5 (p < 0.01). No changes occurred in heart rate, systemic blood pressure or pulmonary wedge pressure. INTERPRETATION: Drug testing with inhalation of iloprost is safe and causes beneficial haemodynamic changes with selective pulmonary vasodilatation. Since the long-term effect of medical intervention is based on the degree of acute pulmonary vascular reactivity, inhalation of iloprost may be a new therapeutic option for severe pulmonary hypertension.

Effect of folic acid treatment on endothelium-dependent vasodilation and nitric oxide-derived end products in hyperhomocysteinemic subjects.

PURPOSE: An elevated plasma homocysteine concentration is an independent risk factor for cardiovascular diseases. In this study, we tested the hypothesis that hyperhomocysteinemia induces endothelial dysfunction mediated, at least in part, through nitric oxide-dependent mechanisms and that folic acid supplementation improves endothelial function in hyperhomocysteinemic subjects. SUBJECTS AND METHODS: Endothelial function was evaluated in healthy controls and hyperhomocysteinemic subjects by measuring plasma levels of the nitric oxide-derived end products nitrite and nitrate and by assessing vasodilatory responses in the skin microcirculation and forearm vasculature. In the subjects with hyperhomocysteinemia, these measurements were repeated after 6 weeks and 12 months of folic acid supplementation. RESULTS: Compared with healthy controls, hyperhomocysteinemic subjects had significantly lower median plasma levels of nitric oxide-derived end products (12.1 microM [range 4.4 to 41.8] versus 24.6 microM [13.6 to 53.2]; P <0.001), a significantly lower endothelium-dependent vasodilatory response to acetylcholine (P <0.01), hyperemic response in the microcirculation (P <0.01), and total forearm blood flow during reactive hyperemia (P = 0.01). There was no significant difference in the endothelium-independent response. Folic acid treatment for 12 months increased the plasma level of nitric oxide-derived end products by 121% (95% confidence interval [CI], 72% to 170%), the vasodilatory response to acetylcholine by 124% (95% CI, 36% to 212%), and the ischemia-mediated hyperemic responses in the microcirculation by 60% (95% CI, 25% to 96%) and in the forearm vasculature by 47% (95% CI, 21% to 73%). CONCLUSIONS: Homocysteine appears to induce its atherogenic effect, at least in part, by depressing endothelial function, possibly through nitric oxide-dependent mechanisms. This effect can be reversed by folic acid supplementation.

Effect of pravastatin on plasma markers of inflammation and peripheral endothelial function in male heart transplant recipients.

Statins appear to have several biologic effects beyond those of lipid metabolism, and we hypothesized that immunomodulating effects of statins are important for the beneficial effects of these medications after heart transplantation. Our findings suggest that pravastatin treatment reduces plasma markers of inflammation and improves peripheral endothelial function in heart transplant recipients, possibly contributing to the observed clinical benefits of statin treatment in these patients.

Omega-3 fatty acids improve blood pressure control and preserve renal function in hypertensive heart transplant recipients.

BACKGROUND: Hypertension and cyclosporine-induced nephrotoxicity are common complications in heart transplant recipients. Omega-3 fatty acids may prevent blood pressure rise early, but have not been studied long-term after heart transplantation. METHODS AND RESULTS: Forty-five clinically stable hypertensive heart transplant recipients were studied 1-12 years after transplantation and randomized in a double-blind fashion to receive either 3.4 g of omega-3 fatty acids daily or placebo for 1 year. Ambulatory 24 h blood pressure monitoring and haemodynamic studies were performed before randomization and at the end of the study. Systolic blood pressure increased by 8+/-3 mmHg (P<0.01) in the placebo group, with a non-significant increase in diastolic blood pressure of 3+/-2 mmHg (P=0.10), accompanied by a 14% increase in systemic vascular resistance (P<0.05). In contrast, no change in blood pressure or systemic vascular resistance was recorded in the omega-3 group. Plasma creatinine increased (P<0.01) and glomerular filtration rate decreased (P<0.05) in the placebo group, while no changes were observed in the omega-3 group. The antihypertensive effect was related to an increase in serum eicosapentaenoic and docosahexaenoic acid. CONCLUSION: Treatment with omega-3 fatty acids may reduce the long-term continuous rise in blood pressure after heart transplantation and may offer a direct or indirect renoprotective effect, making these fatty acids a potentially attractive treatment for post-transplant hypertension.

Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure.

BACKGROUND: Congestive heart failure (CHF) is characterized by enhanced immune activation, and immune-mediated mechanisms may play a pathogenic role in this disorder. Based on the immunomodulatory effects of intravenous immunoglobulin (IVIG), we hypothesized that IVIG could downregulate inflammatory responses in CHF patients and have potential beneficial effects on the left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Forty patients with chronic symptomatic CHF and LVEF of <40%, stratified according to cause (ie, ischemic and idiopathic dilated cardiomyopathy), were randomized in a double-blind fashion to receive therapy with IVIG or placebo for a total period of 26 weeks. Our main findings were that (1) IVIG, but not placebo, induced a marked rise in plasma levels of the anti-inflammatory mediators interleukin (IL)-10, IL-1 receptor antagonist, and soluble tumor necrosis factor receptors; (2) significantly correlated with these anti-inflammatory effects, IVIG, but not placebo, induced a significant increase in LVEF from 26+/-2% to 31+/-3% (P:<0.01), and this was found independent of the cause of heart failure; and (3) N-terminal pro-atrial natriuretic peptide decreased significantly after induction therapy and continued to decrease toward the end of study during IVIG therapy (P:<0.001) but remained unchanged during placebo. CONCLUSIONS: We demonstrated an IVIG-induced change in the balance between inflammatory and anti-inflammatory cytokines that favored an anti-inflammatory net effect in CHF. This effect was significantly correlated with an improvement in LVEF, suggesting a potential for immunomodulating therapy in addition to optimal conventional cardiovascular treatment regimens in CHF patients.

Peripheral endothelial dysfunction in heart transplant recipients: possible role of proinflammatory cytokines.

Endothelium-dependent vasodilation in the peripheral circulation may be impaired in heart transplant recipients (HTx rec). Conflicting results have been obtained and the mechanisms involved have not been examined. In the present study, we examined whether long-time survivors of heart transplantation (Tx) show signs of endothelial dysfunction in the peripheral microcirculation, and further investigated the possible role of endothelium-related markers and proinflammatory cytokines in this process. The vasodilatory responses to acetylcholine (Ach) (endothelium-dependent) and sodium nitroprusside (SNP) (endothelium-independent) were evaluated by skin laser-Doppler perfusion measurements in 63 clinically stable HTx rec 6 yr (range 1-13 yr) after Tx, and compared with 20 healthy controls. Ten HTx rec were also followed prospectively with three repeated measurements during the first year after Tx. Plasma von Willebrand factor, big-endothelin (b-ET), and proinflammatory cytokines were measured by enzyme immunoassays. Vascular responses to both Ach and SNP were significantly attenuated in the HTx rec compared with controls. In longitudinal testing, there was a significant reduction in endothelium-dependent vasodilation, but not independent vasodilation from 1 to 12 months after Tx. Plasma levels of vWF and b-ET, as well as levels of proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-1beta, were all markedly increased in HTx rec. HTx rec responses to Ach were negatively correlated to TNF-alpha levels in plasma (r = -0.39, p < 0.01). Moreover, there was also a significant positive correlation between plasma b-ET and TNF-alpha (r = 0.34, p < 0.01). In the long-term follow-up of HTx rec, endothelial dysfunction is demonstrated by both regulation of blood flow in the skin microcirculation and by raised markers of endothelial activation in plasma. This endothelial dysfunction may be related to enhanced levels of proinflammatory cytokines in these patients.

[Nitric oxide--basal biochemistry and physiological aspects]. / Nitrogenmonoksid--basal biokjemi og fysiologiske aspekter.

Nitric oxide (NO) is a naturally occurring molecule found in a variety of cell types and organ systems, including the cardiovascular, immune and nervous system. NO is normally produced in the endothelium from L-arginine by the constitutive isoform of the NO synthase (cNOS). Thereby, NO is an important regulator of vascular tone, prevents platelet adhesion, aggregation and activation, limits leukocyte adhesion to the endothelium and regulates myocardial contractility. This physiological production of NO is important for blood pressure regulation, blood flow distribution and tissue perfusion. Following injury or certain inflammatory stimuli, the expression of an inducible NO synthase (iNOS) can occur in a great variety of cells. In the last decade research on NO has suggested new treatment strategies for several diseases. In this review we discuss the biochemistry of NO and its basal physiological implications, with special emphasis on NO produced in the endothelium.

[Endothelial function in coronary atherosclerosis and heart failure--the role of nitric oxide in regulation of vasomotor tone]. / Endoteldysfunksjon ved koronar aterosklerose og hjertesvikt--nitrogenmonoksidets rolle i kontroll av kartonus.

The endothelium plays a pivotal role in synthesizing biologically active substances that modulate the vascular tone of underlying smooth muscle cells. Assessment of endothelial function requires measurement of the effects of endothelium-dependent and -independent vasodilators on the systemic microcirculation or resistance vessels. Endothelial dysfunction has been demonstrated early in the course of coronary artery disease, both by studying vasomotor responses in coronary and peripheral vessels, and in the peripheral circulation of patients with chronic heart failure. The impairment of endothelium-dependent vasodilation is related to an abnormality in the endothelium-derived nitric oxide system. The evolving understanding of the complex and probably multifactorial underlying molecular mechanisms of endothelial dysfunction has lead to the identification of potential beneficial therapeutic interventions. Restoration of endothelial function has been associated with fewer episodes of ischaemia in coronary artery disease and improved exercise capacity in heart failure. In light of recent studies we discuss the role of the endothelium, with special emphasis on nitric oxide, in the regulation of vascular tone in coronary artery disease and heart failure.

Possible role of proinflammatory cytokines in heart allograft coronary artery disease.

Transplant coronary artery disease (Tx-CAD) is the main determinant of long-term prognosis after heart transplantation. Immunologic processes may play a central role in the development of Tx-CAD, but the pathogenesis has not been fully clarified. We examined plasma levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL)-1beta and IL-6, and the CC-chemokine macrophage chemoattractant protein-1 (MCP-1) in 62 cardiac allograft recipients undergoing yearly heart catherization with coronary angiography for evaluation of graft disease. In this cross-sectional study, we found significantly increased levels of IL-1beta, IL-6, TNF-alpha, and MCP-1 compared with healthy controls even several years (median 7 years) after transplantation in periods with no intercurrent illness. Although no significant differences were found in plasma levels of IL-1beta and TNF-alpha between patients with (n = 25) and without (n = 37) Tx-CAD, the Tx-CAD group had significantly increased levels of IL-6 and MCP-1 compared with both controls and transplant recipients without Tx-CAD. Increased IL-6 levels compared with controls were found only in patients with Tx-CAD. Finally, while there was no significant relation between Tx-CAD and altered lipid status, the combination of high plasma concentrations of IL-6 or MCP-1 and high low-density lipoprotein cholesterol was strongly associated with increased occurrence of Tx-CAD. These findings indicate that cardiac allograft recipients have a persistent immune activation long term after transplantation. This activation, as particularly reflected in increased MCP-1 and IL-6 levels, may be related to the development of Tx-CAD.