Effect of stentgraft model on aneurysm shrinkage in 1,450 endovascular aortic repairs.

BACKGROUND: Regression of the aneurysmal sac after endovascular repair of abdominal aortic aneurysm (AAA) is an accepted indicator of aneurysm exclusion. This study evaluated the spontaneous decrease in sac diameter over a 10-year period in patients undergoing endovascular aneurysm repair (EVAR) with different stentgrafts. METHODS: 1,450 patients (mean age 73.1 ± 7.7 years; 1,325 male) undergoing EVAR and with a minimum of 1-year computed tomography (CT) imaging were included. Different implanted stentgrafts (n = 622 [42.9%] Zenith, n = 236 [16.3%] AneuRx, n = 179 [12.3%] Talent, n = 83 [5.7%] Endurant, n = 236 [16.3%] Excluder, n = 36 [2.5%] Fortron, 53 [3.7%] Anaconda, n = 5 [0.3%] others) were employed. "Persisting shrinkage" was measured as ≥ 5 mm AAA diameter regression spontaneously persisting or increasing until the end of follow-up without reintervention. Persisting shrinkage among devices was compared with survival and Cox regression analyses. RESULTS: During a median follow-up of 45 months (interquartile range, IQR, 21-79) persisting shrinkage was detected in 768 (53%) aneurysms. Kaplan-Meier estimates of persisting shrinkage were 25.8% at 1 year, 63% at 3 years and 72.6% at 10 years. Persisting shrinkage rates were significantly higher for Zenith (p < .0001), Endurant (p = .013) and new generation Excluder (p < .0001) devices. Cox analyses confirmed that persisting shrinkage rates were independently associated with Zenith (OR 1.33; 95% CI: 1.176-1.514) and Endurant (OR 1.52; 95% CI: 1.108-2.092) stentgrafts and negatively associated with the AneuRx (OR 0.57; 95% CI: 0.477-0.688) device. Survival rates were higher in the persisting shrinkage group: 84.1% vs. 77.8% at 3 years, and 53% vs. 38.1% at 10 years (p < .0001). Freedom from AAA-related-death rate was 100% at 3 years and 99.7% at 10 years in the persisting shrinkage group. CONCLUSIONS: Aneurysm diameter shrinkage can be achieved in most current EVARs with persisting effect at 10 years from repair and indicates the benefit and safety of treatment. Last generation devices seem to be important factors in inducing aneurysm sac shrinkage with similar clinically relevant effects among single models.

Eczema and food allergy in an Italian pediatric cohort: no association with TLR-2 and TLR-4 polymorphisms.

Recent studies have indicated that Toll-like receptor polymorphisms or their impaired signalling, specifically TLR-2 and TLR-4, were correlated with a higher risk for allergy. The purpose of this study is to evaluate the associations of TRL-2 and TRL-4 single nucleotide polymorphisms (SNP) and atopic traits in a cohort of 159 Italian allergic children (102 affected by eczema and 57 by IgE-mediated food allergy) and 147 healthy controls recruited in Rome, Italy. DNA was isolated from the peripheral blood and TLR-2 R753Q/TLR-4 D299G polymorphisms were determined by TaqMan MGB probes using Real-Time PCR technique. In the control group, the TLR-2 polymorphism R753Q had a prevalence of 2.5% while the frequency of the TLR-4 D299G was 12%. None of the 159 allergic patients showed the R753Q SNP. By contrast, 7/57 patients with food allergy (12%) and 6/102 subjects with eczema (6%) carried the TLR-4 mutation. In our cohort, no evidence of correlation between TLR-2 or TLR-4 polymorphism and eczema and food allergy incidence and/or severity was found. Further studies are needed to clarify the possible role of TLR-2 and TLR-4 polymorphism in allergic disease, in Italian children.

Evaluation of microbial contamination of air in two haematology departments equipped with ventilation systems with different filtration devices.

BACKGROUND: Nosocomial infections (NI) are above all due to health-care workers practices, but also the contamination of the environment could lead to their rise in health-care facilities. Introduction. In the last years, the incidence of NI has increased due to a substantial rise in the number of immuno-compromised patients. These patients are often gathered in hospital areas declared at "high risk" of infection such as Hematology and Bone Marrow Transplant ward. In this study, we evaluated microbial contamination of the air in two divisions with high risk patients, focusing on the validity of the air system with correlation to the presence or not of the HEPA absolute filters. METHODS: An environmental surveillance study has been carried out in two Divisions of Haematology, in two different Hospitals. Investigations have been performed by sampling air and by analyzing bacterial and fungal growth on microbiology plates after an incubation period. RESULTS: Unit A, without HEPA filters in the ventilation systems, showed a gradual increase in the bacterial load 20 and 60 days after cleaning of the ventilation system. Mycetes and Aspergilli were not present in basal conditions, at 20 or 60 days after decontamination. Unit B, equipped with HEPA filters placed at the inlet vents, showed extremely low values of the bacterial load either in basal conditions or upon inspection 60 days after cleaning. No mycetes were present. DISCUSSION: From the results obtained, it was evident that following the cleaning operation, the quality of the air is excellent in both types of equipment, since no mycetes were present and the bacterial load was < 20 CFU/mc in all the sites tested. However, although in subsequent controls mycetes were absent in both types of equipment, a great difference in the suspended bacterial load was found: Unit B was close to sterility whereas in Unit A a progressive increase was observed.

Clinical phenotype and beta-cell autoimmunity in Italian patients with adult-onset diabetes.

OBJECTIVE: To characterize the phenotype of a large population of Italian patients with adult onset (> or =40 years) diabetes who were attending outpatient clinics and who were screened for glutamic acid decarboxylase 65 autoantibodies (GADA), protein tyrosine phosphatase IA-2 (IA-2A) and IA-2beta/phogrin (IA-2betaA). DESIGN AND METHODS: This was a cross-sectional study comprising a total of 881 patients, aged < or = 70 years, diagnosed with type 2 diabetes after the age of 40 years, and consecutively recruited in five clinics located in different geographic areas of Italy (Milan, Florence, Rome, Naples and Catania). Their mean disease duration was 8.1 (6.9; s.d.) years. GADA, IA-2A and IA-2betaA were measured with radiobinding assays with in vitro translated S-methionine-labelled glutamic acid decarboxylase 65 (GAD65) or IA-2 or IA-2beta. Anthropometric and clinical data were collected and compared amongst patients with or without autoantibodies. RESULTS: Sixty-three (7.1%) patients had one or more autoantibodies, 58 (6.6%) had GADA, 22 (2.5%) had IA-2A, six (0.7%) had IA-2betaA and 19 (2.15%) had two or more autoantibodies. IA-2A or IA-2betaA, in the absence of GADA, were found in only five patients. Autoantibody-positive patients were more often female (63.5 vs 36.5%; P < 0.009), had higher glycated haemoglobin (Hb A1c) (P < 0.001), lower body mass index (BMI; P < 0.0005) and waist/hip ratio (WHR; P < 0.01); female gender being the main contributor to BMI and WHR. We did not observe any differences in age at diagnosis or duration of disease with respect to the presence or absence of islet autoantibodies. The proportion of patients on insulin therapy was higher in patients with two or more antibodies, compared with those with one antibody only, and no antibodies (P for trend < 0.001), and among patients with GADA, in those with higher antibody titre (73.9% in those with > 10 units vs 42.0% in those with < or = 10 units; P < 0.007). CONCLUSIONS: Patients with adult onset diabetes characterized by autoimmunity to beta-cells showed a clinical phenotype with anthropometric features that differed from those classically observed in patients with type 2 diabetes. The number and titre of autoantibodies, which reflect the severity of autoimmunity and beta-cell impairment, amplified this difference. The usefulness of autoantibody screening in adult-onset diabetes is further emphasized by these findings.

Circulating insulin and insulin growth factor-1 are independent determinants of left ventricular mass and geometry in essential hypertension.

BACKGROUND: It is unclear whether insulin and insulin-like growth factor-1 (IGF-1) are independent determinants of left ventricular (LV) mass in essential hypertension. METHODS AND RESULTS: We studied 101 never-treated nondiabetic subjects with essential hypertension. All had 24-hour noninvasive ambulatory blood pressure (ABP) monitoring and a 75-g oral glucose tolerance test. We determined fasting glucose, insulin, and IGF-1 and postload glucose and insulin 2 hours after glucose. Insulin resistance was estimated by the homeostasis model assessment (HOMA(IR)) formula. LV mass showed an association with body mass index (BMI) (r=0.47; P<0.01), postload insulin (r=0.54; P<0.01), HOMA(IR) (r=0.39; P<0.01), and IGF-1 (r=0. 43; P<0.01) and a weaker association with average 24-hour systolic and diastolic ABPs (r=0.29 and r=0.26; P<0.05) and basal insulin (r=0.31; P<0.05). Relative wall thickness was positively related to IGF-1 (r=0.39; P<0.01) but not to fasting or 2-hour postload insulin, HOMA(IR), and glucose. In a multiple regression analysis, the final LV mass model (R(2)=0.64) included IGF-1, postload insulin, average 24-hour systolic ABP, sex, and BMI. IGF-1 and postload insulin accounted for >40% of variability of LV mass. The final model (R(2)=0.36) for relative wall thickness included IGF-1 (16% total explained variability), average 24-hour systolic ABP, sex, BMI, and age but not insulin and HOMA(IR). CONCLUSIONS: These data indicate that insulin and IGF-1 are powerful independent determinants of LV mass and geometry in untreated subjects with essential hypertension and normal glucose tolerance.

Prognostic value of a new electrocardiographic method for diagnosis of left ventricular hypertrophy in essential hypertension.

OBJECTIVES: We tested the prognostic value of a new electrocardiographic (ECG) method (Perugia score) for diagnosis of left ventricular hypertrophy (LVH) in essential hypertension and compared it with five standard methods (Cornell voltage, Framingham criterion, Romhilt-Estes point score, left ventricular strain, Sokolow-Lyon voltage). BACKGROUND: Several standard ECG methods for assessment of LVH are used in the clinical setting, but a comparative prognostic assessment is lacking. METHODS: A total of 1,717 white hypertensive subjects (mean age 52 years; 51% men) were prospectively followed up for up to 10 years (mean 3.3). RESULTS: At entry, the prevalence of LVH was 17.8% (Perugia score), 9.1% (Cornell), 3.9% (Framingham), 5.2% (Romhilt-Estes), 6.4% (strain) and 13.1% (Sokolow-Lyon). During follow-up there were 159 major cardiovascular morbid events (33 fatal). The event rate was higher in the subjects with than in those without LVH (all p < 0.001) according to all methods except the Sokolow-Lyon method. By multivariate analysis, an independent association between LVH and cardiovascular disease risk was maintained by the Perugia score (hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.5 to 2.8) and the Framingham (HR 1.91, 95% CI 1.1 to 3.2), Romhilt-Estes (HR 2.63, 95% CI 1.7 to 4.1) and strain methods (HR 2.11, 95% CI 1.4 to 3.2). The Perugia score showed the highest population-attributable risk for cardiovascular events, accounting for 15.6% of all cases, whereas the Framingham, Romhilt-Estes and strain methods accounted for 3.0%, 7.4% and 6.8% of all events, respectively. LVH diagnosed by the Perugia score was also associated with an increased risk of cardiovascular mortality (HR 4.21, 95% CI 2.1 to 8.7), with a population-attributable risk of 37.0%. CONCLUSIONS: The Perugia score carried the highest population-attributable risk for cardiovascular morbidity and mortality compared with classic methods for detection of LVH. Traditional interpretation of standard electrocardiography maintains an important role for cardiovascular risk stratification in essential hypertension.

Adverse prognostic significance of concentric remodeling of the left ventricle in hypertensive patients with normal left ventricular mass.

OBJECTIVES: We examined the prognostic significance of concentric remodeling of the left ventricle in patients with essential hypertension and normal left ventricular mass on echocardiography. BACKGROUND: An echocardiographic pattern of concentric remodeling of the left ventricle has been associated with clinical features of increased cardiovascular risk, but the independent prognostic value of this finding in hypertensive patients with normal left ventricular mass has not been established. METHODS: Six hundred ninety-four patients with essential hypertension and normal left ventricular mass (< 125 g/m2) on echocardiography were prospectively followed up for < or = 7.7 years (mean 2.71). Baseline echocardiography and 24-h noninvasive ambulatory blood pressure monitoring were performed in all patients at the time of initial diagnostic evaluation. Concentric remodeling was defined by the thickness of the septum or posterior wall divided by the left ventricular radius at end-diastole > or = 0.45. RESULTS: Prevalence of concentric remodeling was 39.2%. During follow-up there were 29 cardiovascular morbid events. Cardiovascular morbidity, expressed as the combined number of fatal and nonfatal events per 100 patient-years, was 1.53 in the overall study group, 1.12 in the subgroup with normal left ventricular geometry and 2.39 in that with concentric remodeling. After assessment of the independent association with several covariates (age, gender, diabetes, left ventricular mass index, mean clinic blood pressure and mean 24-h ambulatory blood pressure) in Cox proportional hazard models, the risk of cardiovascular morbid events was higher in the group with concentric remodeling than in that with normal geometry (relative risk 2.56, 95% confidence interval 1.20 to 5.45, p < 0.01). CONCLUSIONS: Concentric remodeling of the left ventricle, defined by the thickness of the septum or posterior wall divided by the left ventricular radius at end-diastole > or = 0.45, is an important and independent predictor of increased cardiovascular risk in hypertensive patients with normal left ventricular mass on echocardiography.

Efficacy, safety and acceptability of the new pen needle 33G × 4 mm. AGO 01 study.

OBJECTIVES: Adherence to insulin therapy can be threatened by pain and needle fear. This cross-over randomized non-inferiority trial evaluated a new Pic Insupen 33G × 4 mm needle vs. a 32G × 4 mm needle in terms of metabolic control, safety and acceptability in patients with diabetes treated with insulin. RESEARCH DESIGN AND METHODS: We used a centralized, permuted block randomization, stratified by center and maximum insulin dose per single injection. Subjects used the two needles in two 3 week treatment periods. The primary endpoint was the absolute percentage variation of the blood fructosamine between the two treatments (% |ΔFru|). Additional endpoints were: glycemic variability, total insulin doses, body weight, severe hypoglycemic episodes, leakage at injection sites and pain measured by visual analogue scale. Equivalent glycemic control was defined a priori as % |ΔFru| (including 95% CI) within 20%. RESULTS: Of 87 subjects randomized, 77 completed the study (median age 53.1 [IR 42.3-61.2], median BMI 24.3 Kg/m(2) [IR 21.3-28.5], median duration of insulin therapy [in months] 141.4 (IR 56.3-256.9), median baseline HbA1c 7.9% [IR 7.2-8.8]). The % |ΔFru| was 7.93% (95% CI 6.23-9.63), meeting the non-inferiority criterion. The fasting blood glucose standard deviation was 46.2 (mean 154.6) with the 33G needle and 42.8 (mean 157.3) with the 32G needle (p=0.42). Insulin daily dose and patients' weight did not show any statistically significant variation. We observed 95 episodes of symptomatic hypoglycemia with the 33G needle and 96 with the 32G needle. One episode of severe hypoglycemia was documented in the latter group. As for insulin leakage we observed 37.55 episodes per 100 patient-days with the 33G needle and 32.21 episodes per 100 patient-days with the 32G needle (p=0.31). Patients reported less pain with the 33G × 4 mm needle (p=0.05). STUDY LIMITATIONS: Study sample was mainly composed of adults with type 1 diabetes and study was not blinded. CONCLUSIONS: The 33G needle is not inferior to the 32G needle in terms of efficacy and safety, with reduced pain and no difference in insulin leakage. CLINICAL TRIAL REGISTRATION: NCT01745549.

Prognostic significance of the white coat effect.

The difference between clinic and ambulatory blood pressure (BP) has been used to quantify the pressure reactivity to the doctor's visit (white coat effect). We investigated the prognostic significance of the clinic-ambulatory BP difference in the setting of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study. A total of 1522 subjects contributed 6371 person-years of observation. All subjects had an initial off-therapy diagnostic workup including 24-hour noninvasive ambulatory BP monitoring. The predicted values of ambulatory BP progressively diverged from the identity line (white coat effect of 0 mm Hg) with increasing clinic BP, but the predicted values of clinic BP tended toward the identity line with increasing ambulatory BP. Hence, the clinic-ambulatory BP difference showed a direct association with clinic BP and an inverse association with ambulatory BP. Consequently, a high clinic-ambulatory BP difference predicted both a high clinic and a low ambulatory BP, whereas a low clinic-ambulatory BP difference predicted both a low clinic and a high ambulatory BP. The clinic-ambulatory BP difference showed also a direct association with age. During up to 9 years of follow-up (mean, 4.2 years), there were 157 major cardiovascular morbid events (125 nonfatal and 32 fatal). The rate of total cardiovascular morbid events did not differ (log-rank test) among the four quartiles of the distribution of the clinic-ambulatory BP difference (2.13, 2.92, 2.10, and 2.83 events per 100 patient-years for systolic BP and 2.94, 2.14, 2.58, and 2.16 events per 100 patient-years for diastolic BP). Also, the rate of fatal cardiovascular events did not differ among the four quartiles of the distribution of the clinic-ambulatory BP difference. The clinic-ambulatory BP difference, taken as a measure of the white coat effect, does not predict cardiovascular morbidity and mortality in subjects with essential hypertension.

Early cardiac changes after menopause.

The mechanisms underlying the increased cardiovascular risk after menopause are incompletely known. To investigate whether menopause may induce left ventricular structural and functional adaptations in normotensive and hypertensive women, we compared in a case-control setting (1) 76 untreated hypertensive premenopausal women with 76 postmenopausal women and (2) 30 normotensive premenopausal women with 30 postmenopausal women. Subjects were individually matched by age (+/-5 years; range, 45 to 55), clinic systolic blood pressure (+/-5 mm Hg), and body mass index (+/-2 kgxm-2). All subjects underwent 24-hour blood pressure monitoring and M-mode echocardiography. Age, clinic and daytime blood pressure, body mass index, and smoking habits did not differ between the paired groups. After menopause, blood pressure fall from day to night was lower in both normotensives (10/15% versus 16/21%) and hypertensives (12/17% versus 16/21%) (all P<0.01). Menopause was also associated with a greater left ventricular relative wall thickness (38.8% versus 35.1% in normotensives, 40.2% versus 37.5% in hypertensives) and a reduced midwall fractional shortening (17.3% versus 18.6% in normotensives, 16.6% versus 17.9% in hypertensives) (all P<0.05). We conclude that menopause is associated with blunted day-night blood pressure reduction, impaired left ventricular systolic performance, and concentric left ventricular geometric pattern. These finding are independent of presence or absence of high blood pressure.

Ambulatory pulse pressure: a potent predictor of total cardiovascular risk in hypertension.

A wide pulse pressure (PP) is a marker of increased artery stiffness and high cardiovascular (CV) risk. To investigate the prognostic value of ambulatory PP, which is currently unknown, we studied 2010 initially untreated subjects with uncomplicated essential hypertension (mean age, 51.7 years; 52% men). All subjects underwent baseline procedures including 24-hour noninvasive ambulatory blood pressure (BP) monitoring. The mean duration of follow-up was 3.8 years (range, 0 to 11 years), and CV morbidity and mortality were the outcome measures. There were 200 major CV events (2.61 per 100 person-years), 36 of which were fatal (0.47 per 100 person-years). In the 3 tertiles of the distribution of office PP, the rate of total CV events (per 100 persons per year) was 1.38, 2. 12, and 4.34, respectively, and that of fatal events was 0.12, 0.30, and 1.07 (log-rank test, both P<0.01). In the 3 tertiles of the distribution of average 24-hour PP, the rate of total CV events was 1.19, 1.81, and 4.92, and that of fatal events was 0.11, 0.17, and 1. 23 (log-rank test, both P<0.01). After controlling for several independent risk markers including white coat hypertension and nondipper status, we found that ambulatory PP was associated with the biggest reduction in the -2 log likelihood statistics for CV morbidity (P<0.05 versus office PP). In each of the 3 tertiles of office PP, CV morbidity and mortality increased from the first to the third tertile of average 24-hour ambulatory PP (log-rank test, all P<0.01). Age, left ventricular hypertrophy, and nondipper status were independent predictors of CV mortality, and the further predictive effect of ambulatory PP (P<0.001) was marginally but not significantly superior to that of office PP and average 24-hour systolic BP. We conclude that ambulatory PP is a potent risk marker in essential hypertension. CV morbidity is more closely predicted by ambulatory than by office PP even after control for multiple risk factors.

Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension.

To determine the prognostic significance of ambulatory blood pressure, we prospectively followed for up to 7.5 years (mean, 3.2) 1187 subjects with essential hypertension and 205 healthy normotensive control subjects who had baseline off-therapy 24-hour noninvasive ambulatory blood pressure monitoring. Prevalence of white coat hypertension, defined by an average daytime ambulatory blood pressure lower than 131/86 mm Hg in women and 136/87 mm Hg in men in clinically hypertensive subjects, was 19.2%. Cardiovascular morbidity, expressed as the number of combined fatal and nonfatal cardiovascular events per 100 patient-years, was 0.47 in the normotensive group, 0.49 in the white coat hypertension group, 1.79 in dippers with ambulatory hypertension, and 4.99 in nondippers with ambulatory hypertension. After adjustment for traditional risk markers for cardiovascular disease, morbidity did not differ between the normotensive and white coat hypertension groups (P = .83). Compared with the white coat hypertension group, cardiovascular morbidity increased in ambulatory hypertension in dippers (relative risk, 3.70; 95% confidence interval, 1.13 to 12.5), with a further increase of morbidity in nondippers (relative risk, 6.26; 95% confidence interval, 1.92 to 20.32). After adjustment for age, sex, diabetes, and echocardiographic left ventricular hypertrophy (relative risk versus subjects with normal left ventricular mass, 1.82; 95% confidence interval, 1.02 to 3.22), cardiovascular morbidity in ambulatory hypertension was higher (P = .0002) in nondippers than in dippers in women (relative risk, 6.79; 95% confidence interval, 2.45 to 18.82) but not in men (P = .91). Our findings suggest that ambulatory blood pressures stratifies cardiovascular risk in essential hypertension independent of clinic blood pressure and other traditional risk markers including echocardiographic left ventricular hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Association between persistent pressure overload and ventricular arrhythmias in essential hypertension.

Hypertension is a risk factor for sudden cardiac death, and some data indicate that frequent and complex ventricular arrhythmias may be additional risk markers in hypertensive individuals. We investigated the relation between ventricular arrhythmias and the persistence of increased blood pressure levels over 24 hours in subjects with essential hypertension. We studied 126 never-treated subjects with essential hypertension (83 men) who underwent 24-hour electrocardiographic monitoring, 24-hour ambulatory blood pressure monitoring, and echocardiography. Premature ventricular beats were detected in 71% of the subjects. Compared with subjects in Lown class 0-1, subjects with frequent or complex ventricular arrhythmias (Lown class > or = 2) were older (54 versus 45 years) and had a longer duration of hypertension (5.4 versus 2.8 years), a greater left ventricular mass (147 versus 127 g.m-2), and a blunted nocturnal reduction in ambulatory blood pressure (7%/12% versus 12%/16%). The number of premature ventricular beats over 24 hours was associated with age (r = .25), left ventricular mass (r = .24), and pulse pressure (r = .18) and inversely associated with the present reduction in blood pressure from day to night (r = -.29 for systolic and -.25 for diastolic pressures). In a multiple logistic regression analysis, frequent or complex ventricular arrhythmias (Lown class > or = 2) were predicted by an age > or = 60 years (odds ratio, 10.4 95% confidence interval, 2.4-44.8), left ventricular hypertrophy at echocardiography (odds ratio, 4.2; 95% confidence interval, 1.5-11.6), and a < 10% reduction in blood pressure from day to night ("nondipping" pattern; odds ratio, 2.9;95% confidence interval, 1.2-7.0). We conclude that in addition to the strong effect of age and left ventricular hypertrophy at echocardiography, the persistence of high blood pressure levels over the 24 hours ("nondipping" pattern) is an independent predictor of the frequency and complexity of ventricular arrhythmias in never treated subjects with essential hypertension.

Gly166 in the NK1 receptor regulates tachykinin selectivity and receptor conformation.

We have studied the pharmacological properties of genetically engineered human NK1 tachykinin receptors in which residues at the extracellular surface of the fourth transmembranal domain were substituted with the corresponding amino acids from the NK2 receptor. We show that substitution of G166C:Y167F in the human NK1 receptor induces high affinity binding of a group of tachykinin ligands, known as 'septides' (i.e. neurokinin A, neurokinin B, [pGlu6,Pro9]-substance P6-11 and substance P-methylester). In contrast, binding of substance P and non-peptide antagonists is unaffected by these mutations. This effect parallels that found on the rat receptor and is therefore species specific. Second, we demonstrate that mutation of Gly166 to Cys alone is both necessary and sufficient to create this pan-reactive tachykinin receptor, whereas replacement of Tyr167 by Phe has no detectable effect on the pharmacological properties of the receptor. Furthermore, analysis of the effect of N-ethylmaleimide and dithiothreitol on binding of radiolabelled substance P documents differences in the mode in which this ligand interacts with wild-type and mutant receptors and supports the existence of a mutational induced change in the conformational status of the NK1 receptor.

Predictors of diurnal blood pressure changes in 2042 subjects with essential hypertension.

OBJECTIVE: To determine the independent predictors of day-night blood pressure changes in a large population of subjects with essential hypertension. METHODS: We studied 2042 white untreated subjects with essential hypertension (mean age 52 years, range 17-93, 1052 men) who underwent 24 h ambulatory blood pressure monitoring on an outpatient basis. Night-time workers were excluded from analysis. RESULTS: For both sexes, the changes in systolic and diastolic blood pressures from day to night decreased progressively with age and increased with the reported duration of sleep. The 1207 employed subjects who underwent ambulatory blood pressure monitoring during a usual working day had greater day-night blood pressure differences than did those who did not work (16.2 versus 14.0%). By using multiple regression analysis we assessed the independent association of several variables with the diurnal blood pressure changes. Age and diabetes for both sexes, and clinic blood pressure in men, were inversely associated with the nocturnal fall in blood pressure. The duration of sleep and the occurrence of blood pressure monitoring during a normal work day predicted a greater day-night blood pressure difference for both sexes; smoking predicted a greater nocturnal fall in blood pressure for women. CONCLUSIONS: Age is associated with an important and progressive attenuation of the day-night blood pressure difference in untreated and unrestricted subjects with essential hypertension. Other factors influencing diurnal blood pressure variations include clinic blood pressure, diabetes, the reported duration of sleep, smoking habits and working activity during blood pressure monitoring. These factors should be treated as potential confounders in the analysis of the relationship between diurnal blood pressure changes and target organ damage or prognosis.

Cigarette smoking, ambulatory blood pressure and cardiac hypertrophy in essential hypertension.

OBJECTIVE: To assess the role of blood pressure in the association between cigarette smoking and left ventricular mass in male and female subjects with essential hypertension. DESIGN: A case-control study with matching ratio of 1:4. PATIENTS AND METHODS: We studied 115 heavy smokers (> or = 20 cigarettes/day; 91 men) and 460 non-smokers (364 men) with essential hypertension. Subjects were matched by sex, age (within 5 years) and clinic systolic and diastolic blood pressures (within 5 mmHg). All the subjects underwent 24 h off-therapy non-invasive ambulatory blood pressure monitoring and echocardiography. RESULTS: By matching, clinic blood pressure was nearly identical in smokers and non-smokers (158/99 versus 158/98 mmHg). Daytime ambulatory blood pressure was significantly higher in the smokers than in the non-smokers (150/97 versus 143/93 mmHg), whereas night-time blood pressure did not differ between the two groups (129/79 versus 126/78 mmHg). Smokers had a higher 24 h but not clinic heart rate. Variability of systolic and diastolic blood pressure was slightly greater in smokers when expressed in terms of the standard deviation of the 24 h average (15.9/13.0 versus 14.6/12.2 mmHg), but not after correction for average blood pressure. Left ventricular mass was greater in the smokers than in the non-smokers (119 versus 110 g/m2), and this difference remained after adjustment for clinic blood pressure and other related covariates. However, when clinic blood pressure was replaced by daytime ambulatory blood pressure in the equation, adjusted values of left ventricular mass did not differ between the smokers and the non-smokers (113 versus 112 g/m2). CONCLUSION: In patients with essential hypertension, heavy cigarette smoking (> or = 20 cigarettes/day) is associated with a definite increase in left ventricular mass through a rise in whole-day blood pressure. A pressor mechanism of that type may not be detected by the standard measurement of blood pressure in the clinic, which would make ambulatory blood pressure monitoring a valuable diagnostic tool in this setting.

Adverse prognostic value of a blunted circadian rhythm of heart rate in essential hypertension.

BACKGROUND: Previous studies revealed a direct association between resting heart rate and risk of mortality in essential hypertension. However, resting heart rate is a highly variable measure since it is affected by the alerting reaction to the visit. OBJECTIVE: To investigate whether the heart rate values recorded during the 24 h of ambulatory blood pressure monitoring are independent predictors of survival of uncomplicated subjects with essential hypertension. METHODS: We followed up 1942 initially untreated and uncomplicated subjects with essential hypertension (mean age 51.7 years, 52% men) for an average of 3.6 years (range 0-10 years). All subjects underwent baseline procedures including 24 h non-invasive blood pressure monitoring with simultaneous assessment of heart rate, one reading every 15 min for 24 h. MAIN OUTCOME MEASURES: All-cause mortality and cardiovascular morbidity. RESULTS: During follow-up there were 74 deaths from all causes (1.06 per 100 person-years) and 182 total (fatal plus non-fatal) cardiovascular morbid events (2.66 per 100 person-years). Clinic, average 24 h, daytime and night-time heart rates exhibited no association with total mortality. However, the subjects who subsequently died had had a blunted reduction of heart rate on going from day to night during the baseline examination. After adjustment for age (P < 0.001), diabetes (P < 0.001) and average 24 h systolic blood pressure (SBP, P= 0.002) in a Cox model, for each 10% less reduction in the heart rate from day to night the relative risk of mortality was 1.30 (95% confidence interval 1.02-1.65, P = 0.04). Rates of death were 0.38, 0.71, 0.94 and 2.0 per 100 person-years among subjects in the four quartiles of the distribution of the percentage reduction in heart rate from day to night The baseline day-night changes in the heart rate exhibited an inverse correlation to age and to clinic and ambulatory SBP and a direct association with the day-night changes in blood pressure. The degree of reduction of heart rate from day to night also had an independent inverse association with total cardiovascular morbidity after adjustment for age, diabetes and left ventricular hypertrophy, but this association did not remain significant when average 24 h SBP and the degree of day-night reduction in SBP were entered into the equation. CONCLUSIONS: A flattened diurnal rhythm of heart rate in uncomplicated subjects with essential hypertension is a marker of risk for subsequent all-cause mortality and this association persists after adjustment for several risk factors. For assessing these subjects, a limited and uniformly distributed period of ambulatory heart rate recording during the 24 h is clinically valuable.

Improved electrocardiographic diagnosis of left ventricular hypertrophy.

This study was aimed at improving the performance of standard electrocardiographic criteria of left ventricular hypertrophy (LVH) in essential hypertension using echocardiographic left ventricular mass as reference. In 923 white, untreated hypertensive subjects (mean age 51, prevalence of echocardiographic LVH 34%), sensitivity of electrocardiographic criteria of LVH varied between 9% and 33% and specificity was generally > or = 90%. The sum of Sv3 + RaVL (Cornell voltage) showed the closest association with echocardiographic left ventricular mass (r = 0.48, p < 0.001), and its performance was superior to that of Sokolow-Lyon voltage in a receiver-operating characteristic curve analysis. A modified partition value of the Cornell voltage was tested (> 2.4 mV in men and > 2.0 mV in women), that yielded a good combination between sensitivity (26% in men and 19% in women, overall 22%) and specificity (96% in men and 95% in women, overall 95%). When LVH at electrocardiography was defined as the positivity of at least 1 of the following 3 criteria--Sv3 + RaVL > 2.4 mV in men or > 2.0 mV in women, a typical strain pattern, or a Romhilt-Estes point score > or = 5--sensitivity increased to 39% in men and 29% in women (overall 34%) and specificity decreased to 94% in men and 93% in women (overall 93%). Sensitivity of electrocardiography progressively increased from the first to the fourth quartile of left ventricular mass in subjects with echocardiographic LVH.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic value of left ventricular mass and geometry in systemic hypertension with left ventricular hypertrophy.

To determine the independent prognostic significance of left ventricular (LV) mass and geometry (concentric vs eccentric pattern) in hypertensive subjects with LV hypertrophy at echocardiography, 274 subjects were followed for up to 8.7 years (mean 3.2). All patients had systemic hypertension and LV mass > or = 125 g/body surface area (BSA) and underwent ambulatory blood pressure (BP) monitoring and echocardiography before treatment. Eccentric and concentric hypertrophy were defined by the ratio between LV posterior wall thickness and LV radius at telediastole <0.45 and > or = 0.45, respectively. Age, sex ratio, body mass index, office BP and serum glucose, cholesterol, and triglycerides did not differ between the groups with eccentric (n=145) and concentric (n=129) hypertrophy. Average 24-hour daytime, and nighttime systolic ambulatory BPs were higher in concentric than in eccentric hypertrophy (all p <0.01). LV mass was slightly greater in concentric than in eccentric hypertrophy (157 vs 149 g/BSA, p <0.05). Endocardial and midwall shortening fraction were lower in concentric than in eccentric hypertrophy (96.5% vs 106.0% of predicted and 71.4% vs 89.7% of predicted, respectively; both p <0.01). The rate of major cardiovascular morbid events was 2.20 and 3.34 per 100 patient-years in eccentric and concentric hypertrophy, respectively (log rank test, p=NS). Age >60 and LV mass above median (145 g/BSA) were significant adverse prognostic predictors, while LV geometry (eccentric vs concentric hypertrophy) and ambulatory BP were not. The event rates per 100 patient-years were 1.38 and 3.98, respectively, in the patients with LV mass below and above median (age-adjusted relative risk 2.70; 95% confidence interval [CI] 1.03 to 6.63; p=0.015). In hypertensive subjects with established LV hypertrophy, LV mass, but not its geometric pattern, provides important prognostic information independent of conventional risk markers including office and ambulatory BP.

Value of a simple echocardiographic linear predictor of left ventricular mass in systemic hypertension.

The need for calculations limits the clinical use of left ventricular (LV) mass. Because LV mass is strictly dependent on wall thickness for every given value of LV external dimension, we tested the clinical value of the sum of LV external dimension plus ventricular septal thickness plus posterior wall thickness as predictors of standard LV mass. We studied 295 healthy normotensive subjects and 1,686 subjects with systemic hypertension, followed up for 1 to 9 years. In the normotensive group, the predictor of LV mass showed a very close association with standard LV mass according to an allometric model (LV mass [g] = 0.230 x LV mass predictor [cm]3.01), with 99.7% of LV mass variability explained by the model. Also, in the hypertensive group, the LV mass predictor showed a very close allometric relation to standard LV mass (R2 = 0.998). During follow-up there were 154 cardiovascular morbid events and 50 deaths from all causes. The risk of cardiovascular morbid events and that of death increased to a similar extent with LV mass normalized by body surface area, height or height2.7, as well as with the LV mass predictor. The risk estimates for cardiovascular morbidity and all-cause mortality provided by models including either LV mass predictor or LV mass uncorrected or corrected by height, body surface area, or height2.7 did not show any statistical differences between the different models. In conclusion, the sum of LV external dimension plus ventricular septum thickness plus posterior wall thickness, easily measurable from the M-mode echocardiographic tracing, very closely predicts standard LV mass in adult hypertensive subjects. The prognostic value of this measure does not differ from that of standard LV mass.