Retinal microvascular dysfunction in heart failure.

Aims: Retinal vessel analysis (RVA) represents a novel, non-invasive, and reliable method to study the microcirculation in the eye. The goal of this study was to assess the extent of retinal microvascular dysfunction in patients with chronic heart failure (CHF) compared to controls and established measures of vascular function. Methods and results: In this prospective, single-centre, observational study, 74 patients with compensated CHF (mean age 63.5 ± 11.2 years, 32% female, mean left-ventricular ejection fraction 37 ± 12.8%), 74 patients with cardiovascular risk factors (CVRF; 64.1 ± 12.7 years, 34% female), and 74 healthy controls (HC; 57.8 ± 14.2 years, 35% female) were included. The primary endpoint, flicker-induced dilatation of retinal arterioles (FIDart), was significantly reduced in patients with CHF compared to CVRF and HC (mean FIDart 0.9 ± 0.2 vs. 2.3 ± 0.3 and vs. 3.6 ± 0.3%, respectively, both P < 0.001 before and after propensity score-weighted analysis). Similar differences were seen for venular FID. FIDart was less impaired in patients with dilated compared to ischaemic cardiomyopathy. No significant differences were observed for arteriovenous ratio and flow-mediated dilatation. Impaired FIDven was associated with echocardiographically estimated systolic pulmonary artery pressure and left atrial volume index. Conclusion: Retinal microvascular dilatation in response to flicker light is impaired in CHF. RVA may represent a new and useful method to non-invasively monitor microvascular abnormalities in heart failure in an easy and standardized way without the use of radiation.

SAVE-AMD: Safety of VEGF Inhibitors in Age-Related Macular Degeneration.

OBJECTIVE: To determine whether intraocular treatment with vascular endothelial growth factor (VEGF) inhibitors change systemic endothelial function (EF) in patients with neovascular age-related macular degeneration (AMD). METHODS: In this prospective, randomized, 2-center, double-masked controlled interventional trial, patients with neovascular and dry AMD were enrolled. Eligible neovascular AMD patients received 2 intravitreal loading doses of either ranibizumab 0.5 mg or bevacizumab 1.25 mg at 4-week intervals and were subsequently followed every 4 weeks and treated according to a pro re nata regime for up to 1 year. Patients with dry AMD served as controls. The primary endpoint was the change in EF assessed by flow-mediated dilatation (FMD) after 2 months of treatment with VEGF inhibitors in patients with AMD compared to patients with dry AMD. FMD was assessed with B-mode high-resolution ultrasonography of the left brachial artery. RESULTS: 24 patients with neovascular AMD and 26 patients with dry ADM were included in the trial. Treatment with VEGF inhibitors did not significantly change FMD (from 4.7 ± 2.4 to 3.9 ± 1.9% after 8 weeks, p = 0.07, and to 5.1 ± 2.0% after 1 year; p = 0.93 vs. baseline, respectively). CONCLUSIONS: EF did not significantly differ between patients with neovascular AMD treated with intravitreal VEGF inhibition and patients with dry AMD.

Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling.

In preclinical studies, endothelin receptor A (ETA) antagonists (ETAi) attenuated the progression of heart failure (HF). However, clinical HF trials failed to demonstrate beneficial effects of ETAi. These conflicting data may be explained by the possibility that established HF drugs such as adrenergic receptor blockers interfered with the mechanism of ETAi action in clinical trials. Here we report that mice lacking ETA only in sympathetic neurons (SN-KO) showed less adverse structural remodeling and cardiac dysfunction in response to pathological pressure overload induced by transverse aortic constriction (TAC). In contrast, mice lacking ETA only in cardiomyocytes (CM-KO) were not protected. TAC led to a disturbed sympathetic nerve function as measured by cardiac norepinephrine (NE) tissue levels and [(124)I]-metaiodobenzylguanidine-PET, which was prevented in SN-KO. In a rat model of HF, ETAi improved cardiac and sympathetic nerve function. In cocultures of cardiomyocytes (CMs) and sympathetic neurons (SNs), endothelin-1 (ET1) led to a massive NE release and exaggerated CM hypertrophy compared with CM monocultures. ETA-deficient CMs gained a hypertrophic response through wild-type SNs, but ETA-deficient SNs failed to mediate exaggerated CM hypertrophy. Furthermore, ET1 mediated its effects indirectly via NE in CM-SN cocultures through adrenergic receptors and histone deacetylases, resulting in activation of the prohypertrophic transcription factor myocyte enhancer factor 2. In conclusion, sympathetic ETA amplifies ET1 effects on CMs through adrenergic signaling pathways. Thus, antiadrenergic therapies may blunt potentially beneficial effects of ETAi. Taken together, this may indicate that patients with ß blocker intolerance or disturbed sympathetic nerve function could be evaluated for a potential benefit from ETAi.

The impact of modern noninvasive cardiac imaging on coronary intervention rates.

OBJECTIVES: It remains still unclear whether the use of modern noninvasive diagnostic modalities for evaluation of coronary artery disease (computed tomography coronary angiography (CTCA), nuclear myocardial perfusion imaging (MPI)) were able to change the "diagnostic yield" of invasive coronary angiography (ICA). METHODS: The total number of ICA in the years 2000-2009 was related to the number of percutaneous interventions (PCIs) and we assessed whether there was a significant trend over time using time series analyses. We compared these data with the number of patients undergoing CTCA and nuclear MPI in the same time period. RESULTS: During the 10-year observational period, 23,397 ICA were performed. The proportion of purely diagnostic ICA (without PCI) remained stable over the whole study period (tau = -0.111, P = 0.721). A CTCA program was initiated in 2005 and 1,407 examinations were performed until 2009. Similarly, the number of nuclear MPI increased from 2,284 in the years 2000-2004 to 5,260 in the years 2005-2009 (P = 0.009). CONCLUSION: Despite increasing availability, noninvasive testing modalities did not significantly alter the rate of purely diagnostic ICA, and still are underused as gatekeeper to ICA. Further effort is needed to optimize the use of noninvasive imaging modalities in the work-up process for coronary artery disease.

Haemodynamically irrelevant pericardial effusion is associated with increased mortality in patients with chronic heart failure.

AIMS: Pericardial effusion (PE) is a common finding in cardiac patients with chronic heart failure. The prognostic relevance of a small, haemodynamically non-compromising PE in such patients, however, remains to be determined. METHODS AND RESULTS: All patients referred to our heart failure clinic and having a baseline echocardiography and follow-up clinical visits were included. Patients with a haemodynamically relevant PE, acute myo-/pericarditis, systemic sclerosis, rheumatoid arthritis, heart transplantation, heart surgery within the last 6 months or malignancies within the last 3 years were excluded. Patients with or without a haemodynamically irrelevant PE were compared regarding all-cause mortality as the primary and cardiovascular death or need for heart transplantation as secondary outcomes. A total of 897 patients (824 patients in the control vs. 73 patients in the PE group) were included. In the PE group, left ventricular ejection fraction (LVEF) was lower [31%, interquartile range (IQR): 18.0-45.0] than in controls (34%, IQR: 25.0-47.0; P = 0.04), while the end-systolic diameters of the left ventricle and the left atrium were larger (P = 0.01 and P = 0.001, respectively). Similarly, in patients with PE, the right ventricle (RV) systolic function was lower (P < 0.005 for both the fractional area change and the tricuspid annulus movement), the dimensions of RV and right atrium (RA) were larger (P < 0.05 for RV and P < 0.01 for RA), and the degree of tricuspid regurgitation was higher (P < 0.0001). Furthermore, in the PE group, the heart rate was higher (P < 0.001) and the leukocyte count as well as CRP values were increased (P = 0.004 and P < 0.0001, respectively); beta-blocker use was less frequent (P = 0.04), while spironolactone use was more frequent (P = 0.03). The overall survival was reduced in the PE group compared with controls (P = 0.02). Patients with PE were more likely to suffer cardiovascular death (1-year estimated event-free survival: 86 ± 5 vs. 95 ± 1%; P = 0.01) and to require heart transplantation (1-year estimated event-free survival: 88 ± 4 vs. 95 ± 1%; P = 0.009). A multivariate Cox proportional hazard model revealed the following independent predictors of mortality: (a) PE (P = 0.04, hazard ratio (HR): 1.95, 95% confidence interval (CI): 1.0-3.7), (b) age (P = 0.04, HR: 1.02, 95% CI: 1.0-1.04) and (c) LVEF <35% (P = 0.03, HR: 1.7, 95% CI: 1.1-2.8). CONCLUSION: In chronic heart failure, even minor PEs are associated with an increased risk of all-cause mortality, cardiac death, and need for transplantation.

Statins and the risk of cancer after heart transplantation.

BACKGROUND: Although newer immunosuppressive agents, such as mTOR (mammalian target of rapamycin) inhibitors, have lowered the occurrence of malignancies after transplantation, cancer is still a leading cause of death late after heart transplantation. Statins may have an impact on clinical outcomes beyond their lipid-lowering effects. The aim of the present study was to delineate whether statin therapy has an impact on cancer risk and total mortality after heart transplantation. METHODS AND RESULTS: A total of 255 patients who underwent heart transplantation at the University Hospital Zurich between 1985 and 2007 and survived the first year were included in the present study. The primary outcome measure was the occurrence of any malignancy; the secondary end point was overall survival. During follow-up, a malignancy was diagnosed in 108 patients (42%). The cumulative incidence of tumors 8 years after transplantation was reduced in patients receiving a statin (34% versus 13%; 95% confidence interval, 0.25-0.43 versus 0.07-0.18; P<0.003). Statin use was associated with improved cancer-free and overall survival (both P<0.0001). A Cox regression model that analyzed the time to tumor formation with or without statin therapy, adjusted for age, male sex, type of cardiomyopathy, and immunosuppressive therapy (including switch to mTOR inhibitors or tacrolimus), demonstrated a superior survival in the statin group. Statins reduced the hazard of occurrence of any malignancy by 67% (hazard ratio, 0.33; 95% confidence interval, 0.21-0.51; P<0.0001). CONCLUSIONS: Although it is not possible to adjust for all potential confounders because of the very long follow-up period, this registry suggests that statin use is associated with improved cancer-free and overall survival after cardiac transplantation. These data will need to be confirmed in a prospective trial.

Donor-specific anti-HLA antibodies detected by Luminex: predictive for short-term but not long-term survival after heart transplantation.

In heart transplantation, the clinical significance of pretransplant donor-specific antibodies (DSA) detected by solid phase assay (SPA), which is more sensitive than the conventional complement-dependent cytotoxicity (CDC) assays, is unclear. The aim was to evaluate SPA performed on pretransplant sera for survival after heart transplantation. Pretransplant sera of 272 heart transplant recipients were screened for anti-HLA antibodies using CDC and SPA. For determination of pretransplant DSA, a single-antigen bead assay was performed. The presence of anti-HLA antibodies was correlated with survival. Secondary outcome parameters were acute cellular rejection, graft coronary vasculopathy and ejection fraction. In Kaplan-Meier analysis, SPA-screening did not predict survival (P = 0.494), this in contrast to CDC screening (P = 0.002). However, the presence of pretransplant DSA against HLA class I was associated with decreased short-term survival compared to non-DSA (P = 0.038). ROC curve analysis showed a sensitivity of 76% and specificity of 73% at a cutoff of 2000 MFI. In contrast, the presence of anti-HLA antibodies had no influence on long-term survival, rejection incidence, and graft function. Thus, detection of DSA class I in pretransplant serum is a strong predictor of short-term, but not long-term survival and may help in the early management of heart transplant patients.

Cardiovascular effects of flavanol-rich chocolate in patients with heart failure.

AIMS: Flavanol-rich chocolate (FRC) is beneficial for vascular and platelet function by increasing nitric oxide bioavailability and decreasing oxidative stress. Congestive heart failure (CHF) is characterized by impaired endothelial and increased platelet reactivity. As statins are ineffective in CHF, alternative therapies are a clinical need. We therefore investigated whether FRC might improve cardiovascular function in patients with CHF. METHODS AND RESULTS: Twenty patients with CHF were enrolled in a double-blind, randomized placebo-controlled trial, comparing the effect of commercially available FRC with cocoa-liquor-free control chocolate (CC) on endothelial and platelet function in the short term (2 h after ingestion of a chocolate bar) and long term (4 weeks, two chocolate bars/day). Endothelial function was assessed non-invasively by flow-mediated vasodilatation of the brachial artery. Flow-mediated vasodilatation significantly improved from 4.98 ± 1.95 to 5.98 ± 2.32% (P = 0.045 and 0.02 for between-group changes) 2h after intake of FRC to 6.86 ± 1.76% after 4 weeks of daily intake (P = 0.03 and 0.004 for between groups). No effect on endothelial-independent vasodilatation was observed. Platelet adhesion significantly decreased from 3.9 ± 1.3 to 3.0 ± 1.3% (P = 0.03 and 0.05 for between groups) 2 h after FRC, an effect that was not sustained at 2 and 4 weeks. Cocoa-liquor-free CC had no effect, either on endothelial function or on platelet function. Blood pressure and heart rate did not change in either group. CONCLUSION: Flavanol-rich chocolate acutely improves vascular function in patients with CHF. A sustained effect was seen after daily consumption over a 4-week period, even after 12 h abstinence. These beneficial effects were paralleled by an inhibition of platelet function in the presence of FRC only.

Effects of Pycnogenol on endothelial function in patients with stable coronary artery disease: a double-blind, randomized, placebo-controlled, cross-over study.

AIMS: Extracts from pine tree bark containing a variety of flavonoids have been used in traditional medicine. Pycnogenol is a proprietary bark extract of the French maritime pine tree (Pinus pinaster ssp. atlantica) that exerts antioxidative, anti-inflammatory, and anti-platelet effects. However, the effects of Pycnogenol on endothelial dysfunction, a precursor of atherosclerosis and cardiovascular events, remain still elusive. METHODS AND RESULTS: Twenty-three patients with coronary artery disease (CAD) completed this randomized, double-blind, placebo-controlled cross-over study. Patients received Pycnogenol (200 mg/day) for 8 weeks followed by placebo or vice versa on top of standard cardiovascular therapy. Between the two treatment periods, a 2-week washout period was scheduled. At baseline and after each treatment period, endothelial function, non-invasively assessed by flow-mediated dilatation (FMD) of the brachial artery using high-resolution ultrasound, biomarkers of oxidative stress and inflammation, platelet adhesion, and 24 h blood pressure monitoring were evaluated. In CAD patients, Pycnogenol treatment was associated with an improvement of FMD from 5.3 ± 2.6 to 7.0 ± 3.1 (P < 0.0001), while no change was observed with placebo (5.4 ± 2.4 to 4.7 ± 2.0; P = 0.051). This difference between study groups was significant [estimated treatment effect 2.75; 95% confidence interval (CI): 1.75, 3.75, P < 0.0001]. 15-F(2t)-Isoprostane, an index of oxidative stress, significantly decreased from 0.71 ± 0.09 to 0.66 ± 0.13 after Pycnogenol treatment, while no change was observed in the placebo group (mean difference 0.06 pg/mL with an associated 95% CI (0.01, 0.11), P = 0.012]. Inflammation markers, platelet adhesion, and blood pressure did not change after treatment with Pycnogenol or placebo. CONCLUSION: This study provides the first evidence that the antioxidant Pycnogenol improves endothelial function in patients with CAD by reducing oxidative stress.

Cocoa, blood pressure, and vascular function.

The consumption of a high amount of fruits and vegetables was found to be associated with a lower risk of coronary heart disease and stroke. Epidemiologically, a similar relationship has been found with cocoa, a naturally polyphenol-rich food. Obviously, double blind randomized studies are difficult to perform with cocoa and chocolate, respectively. However, intervention studies strongly suggest that cocoa has several beneficial effects on cardiovascular health, including the lowering of blood pressure, the improvement of vascular function and glucose metabolism, and the reduction of platelet aggregation and adhesion. Several potential mechanisms through which cocoa might exert its positive effects have been proposed, among them activation of nitric oxide synthase, increased bioavailability of nitric oxide as well as antioxidant, and anti-inflammatory properties. It is the aim of this review to summarize the findings of cocoa and chocolate on blood pressure and vascular function.

Nonsteroidal antiinflammatory drugs, acetaminophen, and hypertension.

Selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) as well as acetaminophen belong to the most widely prescribed therapeutic agents worldwide. Their efficacy in pain relief notwithstanding, the use of NSAIDs is associated with an increased cardiovascular risk, which can be partly attributed to their blood pressure raising potential. Adequately powered placebo-controlled trials specifically evaluating the cardiovascular safety of NSAIDs vs. selective COX inhibitors are currently underway. This review summarizes the current knowledge on the cardiovascular effects of NSAIDs and acetaminophen, and their potential clinical consequences.

Acetaminophen increases blood pressure in patients with coronary artery disease.

BACKGROUND: Because traditional nonsteroidal antiinflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, particularly in patients at increased cardiovascular risk. Hence, the aim of this study was to evaluate the safety of acetaminophen in patients with coronary artery disease. METHODS AND RESULTS: The 33 patients with coronary artery disease included in this randomized, double-blind, placebo-controlled, crossover study received acetaminophen (1 g TID) on top of standard cardiovascular therapy for 2 weeks. Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin system, inflammation, and oxidative stress were determined at baseline and after each treatment period. Treatment with acetaminophen resulted in a significant increase in mean systolic (from 122.4±11.9 to 125.3±12.0 mm Hg P=0.02 versus placebo) and diastolic (from 73.2±6.9 to 75.4±7.9 mm Hg P=0.02 versus placebo) ambulatory blood pressures. On the other hand, heart rate, endothelial function, early endothelial progenitor cells, and platelet function did not change. CONCLUSIONS: This study demonstrates for the first time that acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease. Thus, the use of acetaminophen should be evaluated as rigorously as traditional nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors, particularly in patients at increased cardiovascular risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00534651.

Upgrading to resynchronization therapy after chronic right ventricular pacing improves left ventricular remodelling.

AIMS: Chronic right ventricular (RV) pacing may impose ventricular dyssynchrony leading to LV remodelling and is associated with increased morbidity and mortality. Upgrading patients with chronic RV pacing to cardiac resynchronization therapy (CRT) may be considered to restore synchronicity and prevent these deleterious effects. METHODS AND RESULTS: A total of 172 patients from two tertiary centres were analysed over a mean follow-up of 21.7 and 23.5 months after primary CRT implantation (n = 102) and CRT upgrade (n = 70), respectively. In the latter group, mean duration of RV pacing before CRT upgrade was 80.3 months, and ventricular stimulation was >95%. A significant improvement in left ventricular (LV) ejection fraction (10 and 11% absolute increase in primary CRT vs. upgrades, respectively), LV end-diastolic diameter index (-0.15 cm/m(2) vs. -0.2 cm/m(2)), and LV end-systolic diameter (-6.0 vs. -7.0 mm) was observed in both groups, which did not differ between primary CRT recipients and CRT upgrades. Response to CRT upgrade was independent of the underlying rhythm, QRS duration, duration of prior RV pacing, or LV function and size at baseline. Of note, even seven of nine patients with RV pacing >12 years responded favourably to CRT. CONCLUSION: The current study demonstrates that CRT reverses LV remodelling in heart failure patients with chronic RV pacing in a similar way as in primary CRT recipients, even after very long periods of RV pacing. Our data, therefore, may have important implications for the treatment of pacemaker-dependent patients with heart failure, and support the use of CRT in this setting.

Anti-VEGF therapies and blood pressure: more than meets the eye.

"Wet" (also called neovascular) age-related macular degeneration (AMD) is a chronic progressive disease characterized by leakage of fluid or blood from choroidal neovascularization. It remains the leading cause of blindness in the developed world. Vascular endothelial growth factor (VEGF), which plays a key role in the pathogenesis of retinal neovascularization and vessel leakage leading to central vision loss, has emerged as a potential target in the treatment of wet AMD. Importantly, large-scale clinical trials have demonstrated that intravitreal VEGF antagonism prevents vision loss and may even improve visual acuity in patients with neovascular AMD. Because VEGF and its downstream mediator nitric oxide have a well-established cardioprotective role, however, it can be argued that the beneficial effects of VEGF antagonism in the eye may come at the cost of adverse systemic effects, particularly myocardial infarction and stroke.

Virome Sequencing in Patients With Myocarditis.

BACKGROUND: Polymerase chain reaction analyses of cardiac tissues have detected viral sequences in up to 67% of cases of myocarditis. However, viruses have not been implicated in giant cell myocarditis (GCM). Furthermore, efforts to detect viruses implicated in myocarditis have been unsuccessful in more accessible samples such as peripheral blood. METHODS: We used Virome Capture Sequencing for Vertbrate Viruses (VirCapSeq-VERT), a method that simultaneously screens for all known vertebrate viruses, to investigate viruses in 33 patients with myocarditis. We investigated peripheral blood mononuclear cells (n=24), plasma (n=27), endomyocardial biopsies (n=2), and cardiac tissue samples from explanted hearts (n=13). RESULTS: Nine patients (27%) had GCM and 4 patients (13%) had fulminant myocarditis. We found the following viruses in the blood of patients with myocarditis: Epstein Barr virus (n=11, 41%), human pegivirus (n=1, 4%), human endogenous retrovirus K (n=27, 100%), and anellovirus (n=15, 56%). All tissue samples from fulminant myocarditis (n=2) and GCM (n=13) contained human endogenous retrovirus K. CONCLUSIONS: No nucleic acids from viruses previously implicated in myocarditis or other human illnesses were detected in relevant amounts in cardiac tissue samples from GCM or in blood samples from other types of myocarditis. These findings do not exclude a role for viral infection in GCM but do suggest that if viruses are implicated, the mechanism is likely to be indirect rather than due to cytotoxic infection of myocardium.

Evaluation of Myocardial Gene Expression Profiling for Superior Diagnosis of Idiopathic Giant-Cell Myocarditis and Clinical Feasibility in a Large Cohort of Patients with Acute Cardiac Decompensation.

AIMS: The diagnostic approach to idiopathic giant-cell myocarditis (IGCM) is based on identifying various patterns of inflammatory cell infiltration and multinucleated giant cells (GCs) in histologic sections taken from endomyocardial biopsies (EMBs). The sampling error for detecting focally located GCs by histopathology is high, however. The aim of this study was to demonstrate the feasibility of gene profiling as a new diagnostic method in clinical practice, namely in a large cohort of patients suffering from acute cardiac decompensation. Methods and Results: In this retrospective multicenter study, EMBs taken from n = 427 patients with clinically acute cardiac decompensation and suspected acute myocarditis were screened (mean age: 47.03 ± 15.69 years). In each patient, the EMBs were analyzed on the basis of histology, immunohistology, molecular virology, and gene-expression profiling. Out of the total of n = 427 patient samples examined, GCs could be detected in 26 cases (6.1%) by histology. An established myocardial gene profile consisting of 27 genes was revealed; this was narrowed down to a specified profile of five genes (CPT1, CCL20, CCR5, CCR6, TLR8) which serve to identify histologically proven IGCM with high specificity in 25 of the 26 patients (96.2%). Once this newly established profiling approach was applied to the remaining patient samples, an additional n = 31 patients (7.3%) could be identified as having IGCM without any histologic proof of myocardial GCs. In a subgroup analysis, patients diagnosed with IGCM using this gene profiling respond in a similar fashion to immunosuppressive therapy as patients diagnosed with IGCM by conventional histology alone. Conclusions: Myocardial gene-expression profiling is a promising new method in clinical practice, one which can predict IGCM even in the absence of any direct histologic proof of GCs in EMB sections. Gene profiling is of great clinical relevance in terms of a) overcoming the sampling error associated with purely histologic examinations and b) monitoring the effectiveness of therapy.

Angiotensin-converting enzyme inhibition improves vascular function in rheumatoid arthritis.

BACKGROUND: The excess in cardiovascular risk in patients with rheumatoid arthritis provides a strong rationale for early therapeutical interventions. In view of the similarities between atherosclerosis and rheumatoid arthritis and the proven benefit of angiotensin-converting enzyme inhibitors in atherosclerotic vascular disease, it was the aim of the present study to delineate the impact of ramipril on endothelial function as well as on markers of inflammation and oxidative stress in patients with rheumatoid arthritis. METHODS AND RESULTS: Eleven patients with rheumatoid arthritis were included in this randomized, double-blind, crossover study to receive ramipril in an uptitration design (2.5 to 10 mg) for 8 weeks followed by placebo, or vice versa, on top of standard antiinflammatory therapy. Endothelial function assessed by flow-mediated dilation of the brachial artery, markers of inflammation and oxidative stress, and disease activity were investigated at baseline and after each treatment period. Endothelial function assessed by flow-mediated dilation increased from 2.85+/-1.49% to 4.00+/-1.81% (P=0.017) after 8 weeks of therapy with ramipril but did not change with placebo (from 2.85+/-1.49% to 2.84+/-2.47%; P=0.88). Although systolic blood pressure and heart rate remained unaltered, diastolic blood pressure decreased slightly from 78+/-7 to 74+/-6 mm Hg (P=0.03). Tumor necrosis factor-alpha showed a significant inverse correlation with flow-mediated dilation (r=-0.408, P=0.02), and CD40 significantly decreased after ramipril therapy (P=0.049). CONCLUSIONS: Angiotensin-converting enzyme inhibition with 10 mg/d ramipril for 8 weeks on top of current antiinflammatory treatment markedly improved endothelial function in patients with rheumatoid arthritis. This finding suggests that angiotensin-converting enzyme inhibition may provide a novel strategy to prevent cardiovascular events in these patients.