Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial.

BACKGROUND: Antitumor activity of molecular-targeted agents is guided by the presence of documented genomic alteration in specific histological subtypes. We aim to explore the feasibility, efficacy and therapeutic impact of molecular profiling in routine setting. PATIENTS AND METHODS: This multicentric prospective study enrolled adult or pediatric patients with solid or hematological advanced cancer previously treated in advanced/metastatic setting and noneligible to curative treatment. Each molecular profile was established on tumor, relapse or biopsies, and reviewed by a molecular tumor board (MTB) to identify molecular-based recommended therapies (MBRT). The main outcome was to assess the incidence rate of genomic mutations in routine setting, across specific histological types. Secondary objectives included a description of patients with actionable alterations and for whom MBRT was initiated, and overall response rate. RESULTS: Four centers included 2579 patients from February 2013 to February 2017, and the MTB reviewed the molecular profiles achieved for 1980 (76.8%) patients. The most frequently altered genes were CDKN2A (N = 181, 7%), KRAS (N = 177, 7%), PIK3CA (N = 185, 7%), and CCND1 (N = 104, 4%). An MBRT was recommended for 699/2579 patients (27%), and only 163/2579 patients (6%) received at least one MBRT. Out of the 182 lines of MBRT initiated, 23 (13%) partial responses were observed. However, only 0.9% of the whole cohort experienced an objective response. CONCLUSION: An MBRT was provided for 27% of patients in our study, but only 6% of patients actually received matched therapy with an overall response rate of 0.9%. Molecular screening should not be used at present to guide decision-making in routine clinical practice outside of clinical trials.This trial is registered with ClinicalTrials.gov, number NCT01774409.

Adherence to online monitoring of patient-reported outcomes by patients with chronic inflammatory diseases: a feasibility study.

OBJECTIVES: The objective of this report is to investigate the feasibility of collecting patient-reported outcomes (PROs) via e-questionnaires delivered to patients with chronic inflammatory diseases (CIDs). METHODS: Consecutive outpatients with a confirmed diagnosis of systemic lupus erythematosus, primary Sjögren's syndrome or inflammatory bowel disease were followed at two medical departments. Patients received monthly e-mails containing the SF36, Hospital Anxiety and Depression scale and an analogue symptom scale over a six-month period. Participation rate, socio-demographic characteristics and patients' satisfaction were analysed. RESULTS: A total of 128 patients were included (79% female; mean age: 42 ± 12 years). Eighty-two per cent of questionnaires were returned. The monthly participation rate ranged from 89% to 77%, with a six-month attrition rate of 13%. The mean completion rate of questionnaires was 98%. Factors significantly associated with increased answer rate were: married/couple status, greater number of children at home and previous participation in online surveys. The main reasons for non-response were: 'too busy to participate' (35%) and 'away from home Internet access' (31%). Overall, 68% of the participants found the study convenient and 96% agreed to continue at a monthly or bimonthly frequency. CONCLUSION: Online home self-assessment of PROs was feasible in the setting of CIDs. Patients were satisfied and willing to continue the survey. The Internet allows immediate and sophisticated presentation of PROs to clinicians. Future studies are warranted to determine how PRO monitoring may contribute to routine care in CIDs and other diseases.

Different patterns of DNA methylation of the two distinct O6-methylguanine-DNA methyltransferase (O6-MGMT) promoter regions in colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer worldwide. Colorectal cancer incidence differs widely among different geographic regions. In addition to mutational changes, epigenetic mechanisms also play important roles in the pathogenesis of CRCs. O6-methylguanine-DNA methyltransferase (O(6)-MGMT) is a DNA repair protein and in the absence of MGMT activity, G-to-A transition may accumulate in the specific genes such as K-ras and p53. To identify which CpG sites are critical for its downregulation, we analyzed the methylation status of the MGMT gene promoter in two sites in CRC patients. Then we compared the frequency of their methylation changes with the results of our previously reported K-ras gene mutation, APC2 and p16 methylation. MGMT methylation was examined in 92 tumor samples. A methylation specific PCR (MSP) method was performed for two loci of MGMT gene which described as MGMT-A and MGMT-B. The prevalence of MGMT-A, and MGMT-B methylation was 49/91 (53.8%), and 83/92 (90.2%), respectively. We detected high frequency of MGMT-B but not MGMT-A methylation in tumor tissues with APC2 methylation. Our results showed that MGMT-B methylation is significantly associated with K-ras gene mutation rather than MGMT-A (p = 0.04). Simultaneously, an inverse correlation was found between p16 and MGMT-B methylation simultaneously (p = 0.02). Our study indicated that hypermethylation of the specific locus near the MGMT start codon is critical for cancer progression. MGMT-B assessment that is associated with K-ras mutation can have a prognostic value in patients with CRC.

Immune checkpoint inhibitor treatment of a first cancer is associated with a decreased incidence of second primary cancer.

BACKGROUND: Second primary cancers (SPCs) are diagnosed in over 5% of patients after a first primary cancer (FPC). We explore here the impact of immune checkpoint inhibitors (ICIs) given for an FPC on the risk of SPC in different age groups, cancer types and treatments. PATIENTS AND METHODS: The files of the 46 829 patients diagnosed with an FPC in the Centre Léon Bérard from 2013 to 2018 were analyzed. Structured data were extracted and electronic patient records were screened using a natural language processing tool, with validation using manual screening of 2818 files of patients. Univariate and multivariate analyses of the incidence of SPC according to patient characteristics and treatment were conducted. RESULTS: Among the 46 829 patients, 1830 (3.9%) had a diagnosis of SPC with a median interval of 11.1 months (range 0-78 months); 18 128 (38.7%) received cytotoxic chemotherapy (CC) and 1163 (2.5%) received ICIs for the treatment of the FPC in this period. SPCs were observed in 7/1163 (0.6%) patients who had received ICIs for their FPC versus 437/16 997 (2.6%) patients receiving CC and no ICIs for the FPC versus 1386/28 669 (4.8%) for patients receiving neither CC nor ICIs for the FPC. This reduction was observed at all ages and for all histotypes analyzed. Treatment with ICIs and/or CC for the FPC are associated with a reduced risk of SPC in multivariate analysis. CONCLUSION: Immunotherapy with ICIs alone and in combination with CC was found to be associated with a reduced incidence of SPC for all ages and cancer types.

FOLFIRINOX in patients with peritoneal carcinomatosis from pancreatic adenocarcinoma: a retrospective study.

Background: Peritoneal carcinomatosis (pcm) in metastatic pancreatic ductal adenocarcinomas (mpdac) is frequently encountered in day-to-day practice, but rarely addressed in the literature. The objective of the present study was to describe the management and outcome of patients diagnosed with pcm. Methods: Data for all consecutive patients with mpdac treated in our centre between 1 January 2014 and 31 August 2015 were analyzed retrospectively. Computed tomography imaging was centrally reviewed by a dedicated radiologist to determine the date of pcm diagnosis. Results: The analysis included 48 patients. Median age in the group was 61 years, and 41 patients had an Eastern Cooperative Oncology Group performance status (ecog ps) of 0-1. All patients presented with pcm either synchronously (group 1) or metachronously (group 2). Those groups differed significantly by baseline ecog ps and neutrophil-to-lymphocyte ratio (nlr), with ecog ps being poorer and nlr being higher in group 1. In addition to pcm, the main sites of metastasis were liver (62.5%) and lungs (31.3%). First-line chemotherapy in 36 patients (75%) was folfirinox (fluorouracil-irinotecan-leucovorin-oxaliplatin). The median overall survival for the entire population was 10.81 months [95% confidence interval (ci): 7.16 months to 14.16 months]; it was 13.17 months (95% ci: 5.9 months to 15.4 months) for patients treated with folfirinox. Median overall survival was 7.13 months (95% ci: 4.24 months to 10.41 months) for patients in group 1 and 14.34 months (95% ci: 9.79 months to 19.91 months) for patients in group 2, p = 0.1296. Conclusions: Compared with other metastatic sites, synchronous pcm seems to be a poor prognostic factor. It could be more frequently associated with a poor ecog ps and a nlr greater than 5 in this group of patients. In patients with mpdac and pcm, either synchronous or metachronous, folfirinox remains an efficient regimen.

Mental stress impairs endothelial vasodilatory function by a beta-adrenergic mechanism.

Mental stress has been shown to impair endothelium-dependent vasodilation (EDV) in the human forearm. The aim of this study was to investigate if this response could be blunted by local infusions of beta-blockade (propranolol), alpha-blockade (phentolamine), or neurogenic blockade. Thirty-one young healthy volunteers underwent forearm blood flow (FBF) measurements, using venous occlusion plethysmography, during local intra-arterial infusions of metacholine (MCh; inducing EDV) and sodium nitroprussid (SNP; inducing endothelial-independent vasodilation [EIDV]), respectively. These measurements were repeated during a 5-min mental arithmetic stress test without (n = 8) or with concomitant local infusion of propranolol (n = 7) or phentolamine (n = 8) in the forearm or during axillary plexus blockade (n = 8). An index of endothelial vasodilatory function (EFI) was calculated as the EDV to EIDV ratio. Mental stress impaired EDV significantly (p < .05), and as a result, EFI was significantly reduced (p = .02). This effect on EFI could be blocked by propranolol and neurogenic blockade but not by phentolamine (p < .05). Thus, impairment of endothelial vasodilatory function induced by mental stress could be blocked by beta-adrenergic, but not alpha-adrenergic, receptor blockade.

Endothelium-dependent vasodilation is related to the fatty acid composition of serum lipids in healthy subjects.

The fatty acid (FA) composition of the serum lipids has been associated with cardiovascular disease (CVD). As an attenuated endothelium-dependent vasodilation (EDV) has been suggested as an early marker of atherosclerosis, we investigated the relationships between the proportion of FA in serum lipids (cholesterol esters and phospholipids) together with the levels of serum LDL- and HDL-cholesterol and triglycerides and EDV, as well as endothelium-independent vasodilation (EIDV). Fifty-six healthy subjects (31 men and 25 women), aged between 20 and 69 years, underwent measurements of forearm blood flow (FBF) at rest and during local infusion of 2 and 4 microg/min of metacholine (Mch, evaluating EDV), 5 and 10 microg/min of sodium nitroprusside (SNP, evaluating endothelium-independent vasodilation, EIDV) using venous occlusion plethysmography. An index of endothelial function was calculated as the ratio between EDV and EIDV. The proportion of palmitic (16:0) and palmitoleic (16:1) acids were inversely related (r=-0.35 and -0.35, P<0.01 for both), while linoleic acid (18:2 n6) and the HDL-cholesterol concentration were positively related (r=0.35 and 0.36, P<0.01 for both) to the endothelial function index. In multiple regression analysis also including age and gender, palmitoleic acid and HDL-cholesterol were significant independent predictors of endothelial function. Alfa-linolenic acid (18:3 n3) was positively correlated to both EDV and EIDV (r=0.40 and 0.43, P<0.01 for both), indicating a protective effect of this essential FA on vasodilation in general. It is concluded that the FA composition of serum lipids, partly reflecting the composition of dietary fat and previously associated with the development of CVD, was associated with endothelial function in apparently healthy subjects.

Soluble intercellular adhesion molecule-1 is related to endothelial vasodilatory function in healthy individuals.

OBJECTIVE: To investigate the associations between markers of systemic and vascular inflammation, and indicators of vascular morphology and function. METHODS: In 59 apparently healthy individuals, we measured serum levels of highly sensitive C-reactive protein (hsCRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Endothelium-dependent (EDV) and -independent (EIDV) vasodilatation was evaluated in the forearm by venous occlusion plethysmography and local infusions of methacholine and sodium nitroprussid. Endothelial function index (EFI) was expressed as the EDV/EIDV ratio. The intima-media thickness (IMT) of the common carotid artery was investigated with ultrasound (far wall). RESULTS: EFI was inversely related only to ICAM-1 (r=-0.31, P<0.02) by univariate analysis. This association remained significant after adjustment for age, sex, blood pressure, smoking and serum cholesterol. EFI did not relate to hsCRP, VCAM-1 or E-selectin. Neither hsCRP, nor the adhesion molecules were significantly related to carotid artery IMT. CONCLUSION: ICAM-1 was related to endothelial vasodilatory function, but not to IMT, suggesting that endothelial inflammatory activation is related to an impaired vascular relaxation in apparently healthy individuals.

Captopril, but not nifedipine, improves endothelium-dependent vasodilation in hypertensive patients.

The present study aimed to investigate the influence of the angiotensin-converting enzyme (ACE)-inhibitor captopril and the Ca-antagonist nifedipine on endothelium-dependent vasodilation (EDV) in the forearm of hypertensive patients. Twenty-three middle-aged untreated hypertensive patients underwent evaluation of EDV and endothelium-independent vasodilation (EIDV) in the forearm, by means of local intra-arterial infusions of methacholine (MCh, evaluating EDV) and sodium-nitroprusside (SNP, evaluating EIDV), before and 1 h after intake of either captopril (25 mg) or nifedipine (10 mg) in a randomised, double-blind fashion. A matched normotensive control group was investigated at baseline conditions only. Five of the hypertensives were also evaluated after 3 months of treatment with captopril 25 mg twice daily in an open pilot study. First, the vasodilation induced by methacholine (MCh), but not SNP, was significantly attenuated in the hypertensive patients compared to the normotensive controls (P < 0.001 at MCh 4 microg/min). Second, although the two drugs induced a similar decline in blood pressure (BP) 1 h after administration (-11 to 10 mm Hg/-8 to 7 mm Hg), captopril significantly potentiated the vasodilator response to MCh (+32+/-13%, MCh 4 micr og/min, P < 0.01) but not SNP, while nifedipine did not significantly alter the response to either MCh or SNP. The improvement in vasodilator response to MCh induced by captopril was closely related to the reduction in BP (r = 0.72, P < 0.01). Third, in the pilot study, 3 months of captopril treatment induced a significant potentiation of the vasodilator response to MCh (+34+/-17%, MCh 4 microg/min, P < 0.05) in parallel with a significant BP reduction (-22+/-24/13+/-13 mm Hg, P < 0.05), while the response to SNP was unchanged. In conclusion, the present study confirmed that essential hypertension is associated with a defect in EDV. Furthermore, an improvement in EDV was seen in hypertensive patients shortly after administration of captopril, but not nifedipine. In addition, a significant beneficial effect on EDV was seen in a small pilot study during long-term treatment with captopril.

Blood flow is an important determinant of forearm glucose uptake following a mixed meal.

Insulin-mediated vasodilation has been suggested to be of importance for glucose uptake during normoglycemic hyperinsulinemia. If this also is valid after an ordinary mixed meal remains to be evaluated. Forearm blood flow (FBF) and forearm glucose uptake change (evaluated by venous occlusion plethysmography) and glucose arteriovenous differences were evaluated over 120 minutes in 10 healthy volunteers following an ordinary mixed meal (700-900 kcal, 34% of energy from fat). Fasting arterial glucose level was 4.9+/-0.9 mmol/l, and the maximum glucose level was reached 30 minutes after the start of ingestion (6.6+/-0.8 mmol/l, p<0.0001). Plasma insulin levels were increased four-fold. FBF increased rapidly within 20 minutes after the start of ingestion and reached its maximum after 50 minutes (94% higher than baseline level, p<0.01). After 2 hours FBF was still substantially elevated (75% above baseline level, p<0.01). Forearm glucose uptake increased fivefold already after 20 minutes ( p<0.01). During the 2 hours, the increase in FBF contributed to 41% of the forearm glucose uptake ( p<0.05). The present study showed that the increase in FBF seen after an ordinary mixed meal is important for the change in forearm glucose uptake. These results support the view that modulation of limb blood flow is a determinant of glucose uptake.

Local vasodilatation with metacholine, but not with nitroprusside, increases forearm glucose uptake.

Insulin is known to increase blood flow in parallel to glucose uptake in skeletal muscle. However, it is not known if an increase in blood flow by itself is associated with an increase in glucose uptake in the absence of hyperinsulinemia. To investigate further this matter, the effect of increased blood flow on forearm glucose uptake was studied in the fasting state during intra-arterial infusions of two different vasodilators, metacholine and nitroprusside, in 19 hypertensive subjects. Both metacholine (4 microg/min) and nitroprusside (10 microg/min) increased resting forearm blood flow, measured by venous occlusion plethysmography, to a similar degree (180 % and 170 %, respectively, p<0.0001 for both). However, metacholine infusion increased the forearm glucose uptake from 2.0+/-0.9 (S.D.) during rest to 5.5+/-3.0 umol/min/100 ml tissue (p<0.0001), while no significant change in glucose uptake was seen during nitroprusside infusion (2.3+/-1.4 micromol/min/100 ml tissue). In conclusion, vasodilatation induced by metacholine, but not by nitroprusside, increased glucose uptake in the forearm of hypertensive patients. Thus, an increase in forearm blood flow does not necessarily improve glucose uptake in the forearm during the fasting state.

[Non-cirrhotic ascites: pathophysiology, diagnosis and etiology]. / L'ascite non liée à la cirrhose : physiopathologie, diagnostic et étiologies.

Ascites, in 20% of cases, is not linked to liver cirrhosis. The pathophysiology is most often different. The understanding of these pathophysiological mechanisms can lead to etiologic diagnosis. The diagnostic approach is mainly based on the biological study of ascites, especially protein concentration and albumin gradient between serum and ascites. In Western countries, tumors and heart diseases are the predominant causes, while developing countries are mainly concerned by infectious diseases, among which tuberculosis is the leading cause. Other uncommon causes must be recognized, as ascites may be the presenting feature of the disease. Their knowledge will facilitate the therapeutic approach.

Short-term effects of smoking and nicotine chewing gum on endothelium-dependent vasodilation in young healthy habitual smokers.

Smoking is a major risk factor for coronary and peripheral vascular disease. This study was designed to investigate the short-term effects of smoking and nicotine gum on endothelium-dependent (EDV) and -independent (EIDV) vasodilation in the forearm of young habitual smokers. In 10 subjects, forearm blood flow (FBF) during local infusion of metacholine (4 microg/min, evaluating EDV) and sodium nitroprusside (10 microg/min, evaluating EIDV) was assessed before and at 10 min (early phase) and 30-50 min (plateau phase) after the initiation of smoking, using forearm venous occlusion plethysmography. Six subjects underwent similar measurements of FBF before and 30 min after chewing a nicotine gum (4 mg). As a change in blood pressure was expected, forearm vascular resistance (FVR) was used to calculate EDV and EIDV. FVR during metacholine infusion increased from 4.6 +/- 1.4 SD to 5.9 +/- 2.1 mm Hg/ml/min/100 ml tissue during the early and to 5.0 +/- 1.6 mm Hg/ml/min/100 ml tissue at the plateau phase of smoking (p < 0.01 for both vs. baseline) and from 4.5 +/- 1.6 to 5.2 +/- 1.6 mm Hg/ml/min/100 ml tissue after chewing the nicotine gum (p < 0.01). No significant changes in EIDV were seen after smoking or the nicotine gum. When all data were analyzed together, plasma nicotine levels and blood pressure were both independent predictors of endothelial function (p < 0.001 for both). In conclusion, cigarette smoking induced a dose-dependent attenuation in EDV, being maximal shortly after initiation of smoking and persisting up to 30-50 min. Nicotine chewing gum induced a similar impairment in EDV.

Mental stress opposes endothelium-dependent vasodilation in young healthy individuals.

Mental stress has been shown to induce myocardial ischemia in people with coronary heart disease (CHD), both in the laboratory and in daily life. In order to investigate the role of the endothelium in the regulation of blood flow during stress, the endothelium-dependent (EDV) and endothelium-independent (EIDV) vasodilation was examined in the forearms of healthy people during a mental arithmetic test (MAT), a cold pressor test (CP) and an isometric handgrip test (ISO). A total of 10 young healthy volunteers (four men and six women, aged 20-25 years) underwent measurements of forearm vascular resistance (FVR) during local intraarterial infusions of methacholine (MCh; inducing EDV) and sodium nitroprusside (SNP; inducing EIDV) at rest and during the different forms of stress by the use of venous occlusion plethysmography. MAT induced a significant increase in FVR during MCh infusion (4 microg/min, from 3.5 +/- 0.7 at rest to 4.2 +/- 1.4 mmHg/ml per min per 100 ml tissue during MAT; p < 0.01), while FVR during SNP infusion was unchanged by MAT. CP induced a significant increase in FVR during infusions with both MCh and SNP compared to resting levels (p < 0.01 for both), while ISO induced a significant increase in FVR during MCh infusion (p < 0.05) and a smaller increase in FVR during SNP infusion. When the SNP to MCh FVR ratio was used as an index of endothelial function, only MAT impaired endothelial function significantly (p < 0.01). In conclusion, mental stress induced by an arithmetic task selectively opposed EDV in the forearms of young healthy people, while cold pressor and isometric handgrip tests induced a more general attenuation in vasodilatation.

Effects of age, gender and metabolic factors on endothelium-dependent vasodilation: a population-based study.

OBJECTIVES: A progressive decline in endothelium-dependent vasodilation (EDV) in the human forearm with age has previously been reported. The aim of this study was to evaluate the interplay between age, gender and metabolic factors on EDV in healthy subjects in a population-based study. SETTING: Tertiary university hospital. SUBJECTS AND DESIGN: Thirty-six healthy men and 30 women, aged 20-69 years, underwent measurements of forearm blood flow (FBF) at rest and during local infusions of 2 and 4 microg min-1 of metacholine (evaluating EDV) and 5 and 10 microg min-1 of sodium nitroprusside (evaluating endothelium-independent vasodilation, EIDV) and during reactive hyperaemia by venous occlusion plethysmography. RESULTS: Age was inversely related to EDV (r = - 0.41, P < 0.05 in men; r = - 0.61, P < 0.01 in women) and maximal FBF during reactive hyperaemia in both men and women. EIDV was significantly related to age in an inverse way in women only. EDV was more pronounced in females than in males before menopause (48 +/- 3 SD years, 635 +/- 186 vs. 502 +/- 269% in males, P < 0.05), but similar in women and men thereafter (374 +/- 141 vs. 370 +/- 185% in men). The slope of the regression line for the relationship between age and EDV was flatter in premenopausal than in postmenopausal women (- 2.3 vs. - 6.4), whilst this slope was similar in younger and older men (- 5.5 vs. - 5.3). In multiple regression analysis, fasting blood glucose levels and the waist/hip ratio remained the only significant predictors of EDV in men (P < 0.01 for both), whilst age was the only significant independent predictor of EDV in women (P < 0.01). CONCLUSION: The interplay between age and metabolic factors as determinants of endothelial function is different in healthy men and women.

Methodological aspects of the evaluation of endothelium-dependent vasodilatation in the human forearm.

The present study, involving 56 healthy subjects from a health screening, was undertaken to address some methodological questions regarding the measurement of endothelial function using local intra-arterial infusions of metacholine (2 and 5 micrograms min-1) to evaluate endothelium-dependent vasodilatation, and sodium nitroprusside (SNP, 5 and 10 micrograms min-1) to evaluate endothelium-independent vasodilatation. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. The ratio of FBF during the highest dose of metacholine to FBF during the highest dose of SNP was used as an index of endothelial function. In 10 young volunteers the procedure was repeated after 2 h and again after 3 weeks in order to study short-term and long-term reproducibility of the method. Neither the vasodilatatory response to metacholine (r = 0.006) nor that to SNP (r = 0.08) was related to resting FBF. Neither the circumference nor the length of the arm was related to endothelial function (r = 0.01-0.11), as evaluated by the FBF on metacholine to nitroprusside ratio (mean 1.3 +/- 0.3 SD). The use of a wrist cuff to exclude hand circulation, or not, did not influence the evaluation of endothelial function significantly. Maximal FBF after 3 min of arterial occlusion of the forearm was significantly related to blood flow during both metacholine (r = 0.53, P < 0.01) and nitroprusside infusion (r = 0.36, P < 0.05), but not to the FBF on metacholine to nitroprusside ratio (r = 0.01). The short-term and long-term reproducibility of FBF during vasodilatation with metacholine and SNP was good (r = 0.89-0.97, P < 0.001), while the individual measurements for resting FBF were less reproducible when repeated after 3 weeks (r = 0.34). In conclusion, endothelial function was not related to resting FBF, nor to the arm circumference or length. No major difference was seen whether endothelial function was evaluated with or without exclusion of the hand circulation. Maximal FBF during reactive hyperaemia was not related to endothelial function.

Left ventricular hypertrophy is associated with an attenuated endothelium-dependent vasodilation in hypertensive men.

To investigate the relationship between left ventricular hypertrophy (LVH) and endothelium-dependent vasodilation (EDV), 30 untreated hypertensive patients, 18 treated hypertensives (53 +/- 7 years, all males) and 26 age-and sex-matched healthy normotensive controls, underwent evaluation of EDV and endothelium-independent vasodilation (EIDV) in the forearm, by means of local intra-arterial infusions of methacholine (MCh, evaluating EDV) and sodium nitroprusside (SNP, evaluating EIDV). Forearm blood flow was measured by venous occlusion plethysmography and LVH was measured by echocardiography. The reduction in forearm vascular resistance during MCh infusion (4 microg/min) was significantly smaller in the hypertensive patients with LVH when compared to those without LVH, both in the untreated (-61 +/- 12%, n = 19 vs -72 +/- 4%, n = 11, p < 0.01) and in the treated group (-60 +/- 15%, n = 11 vs -75 +/- 5%, n = 7, p < 0.01). Thereby, EDV was significantly impaired only in the hypertensive patients with LVH when compared to controls (-77 +/- 7% at MCh 4 microg/min, p < 0.001). EIDV was not significantly different between patients with and without LVH and controls. In conclusion, the presence of LVH was related to endothelial dysfunction, both in untreated and treated hypertensive patients, suggesting either a role for endothelial function in the development of LVH, or that a dysfunctional endothelium and LVH are coexisting markers of a more severe hypertensive disease.

Ambulatory blood pressure and endothelium-dependent vasodilation in hypertensive patients.

Endothelial function is important for local vascular regulation and an abnormal endothelium-dependent vasodilatation (EDV) has been observed in subjects with essential hypertension. As ambulatory blood pressure (ABP) is more closely related to target organ damage than office blood pressure, this study investigated also if 24-h ABP is more closely related to an impaired EDV than office blood pressure recordings. In a group of 25 untreated patients with essential hypertension and an age- and sex-matched control group (n = 21) endothelial function was evaluated by measurements of forearm blood flow (FBF) during local intra-arterial infusions of metacholine (evaluating EDV) and sodium nitroprusside (evaluating endothelium independent vasodilation, EIDV). FBF was measured with venous occlusion plethysmography. Both office mean artery pressure (MAP; r= -0.57, p < 0.001) and 24-h ABP (r = 0.40, p < 0.01) were related to the endothelial vasodilator function (EDV to EIDV ratio) in an inverse way, but ABP was not superior to office blood pressure recordings. Within the hypertensive group, pronounced white-coat effect (office minus daytime ABP) was associated with a reduced,EDV (r= 0.41, p < 0.05). The degree of night-time decline in blood pressure ("dipping") showed no correlation to EDV. In conclusion, the finding that ABP was no more closely related to the endothelial vasodilator function than office blood pressure recordings might be due to an increased mental alertness affecting EDV in some hypertensive subjects, as suggested by the finding of a reduced EDV in those with a pronounced white-coat effect.

Endothelium-dependent vasodilation and structural and functional changes in the cardiovascular system are dependent on age in healthy subjects.

The aim of this study was to evaluate possible associations between endothelium-dependent vasodilatation (EDV) and cardiovascular structure and function. EDV could influence peripheral resistance and be affected by atherosclerosis and might thereby influence indices of cardiovascular structure and function. In a group of 31 apparently healthy men and 25 women (age range 20-69 years), EDV was evaluated by infusion of metacholine (4 micrograms min-1), and endothelium-independent vasodilatation (EIDV) was assessed by nitroprusside infusion (SNP, 10 micrograms min-1) in the brachial artery. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Left ventricular (LV) geometry and function and the intima-media thickness in the carotid artery were assessed by ultrasonography. The stroke index to pulse pressure ratio was used to evaluate arterial compliance. Several indices of cardiovascular structure and function were found to be related to an index of endothelial function, the EDV to EIDV ratio. Furthermore, left ventricular mass (LVM), the atrio-ventricular plane displacement, E/A ratio, IVRT, the intima-media thickness of the carotid artery and arterial compliance were all significantly related to both EDV and EIDV in women. However, most indices of cardiovascular structure and function, as well as endothelial function, change with age and only the relation between LV diastolic function and endothelial function in men remained significant (P < 0.05) after including age in multiple regression analysis. Age was related to both cardiovascular structure and function, as well as to endothelial function. Multiple regression analysis showed that ageing generally affects cardiovascular characteristics and endothelial function in parallel in these healthy subjects.

Endothelin plays an important role in the endothelium-dependent vasodilatation in the human forearm.

UNLABELLED: Endothelium-dependent vasodilatation (EDV) in humans has been evaluated mainly by local infusion of a muscarinic-receptor agonists in the forearm. It has been postulated that the function of the vasodilator nitric oxide (NO) can be evaluated with this technique. However, the role of the vasoconstrictor endothelin in this model has not been investigated. METHODS: Ten male hypertensive and seven male normotensive subjects were subjected to measurements of forearm blood flow (FBF) by venous occlusion plethysmography during local intra-arterial infusion of metacholine (4 microg/min) or nitroprusside (10 microg/min). In parallel, forearm venous plasma endothelin (ir-ET) was determined. RESULTS: Metacholine and nitroprusside increased FBF 2.3 and 2.2 times the baseline level (6.6+/-2.8 SD ml/min/100 ml tissue) in hypertensive subjects and 5.1 times the baseline level (2.7+/-3.0 ml/min/100 ml tissue) for both drugs in the normotensive subjects. None of the drugs induced any significant changes in ir-ET levels in any of the groups (baseline 1.5+/-0.4 pmol/l in hypertensive and 1.1+/-1.2 pmol/l in normotensive subjects). However, in the hypertensive subjects, the individual change in venous ir-ET levels during infusion with metacholine, but not with nitroprusside, was inversely related to the degree of vasodilatation induced by this agent (r = -0.71, p < 0.02). A similar correlation coefficient (r=-0.69) was found in healthy subjects. CONCLUSION: Muscarinic-receptor-agonist-stimulated vasodilatation in the human forearm, thought mainly to reflect NO synthesis, was inversely related to the change in endothelin levels, suggesting an important role for this endothelium-derived vasoconstrictor in this model of EDV.