Weight loss facilitates reduction of left ventricular mass in obese hypertensive patients: The Campania Salute Network.

BACKGROUND AND AIMS: Reduction of left ventricular mass index (LVMi) during antihypertensive treatment is less likely to occur in obese subjects. The aim of the study was to assess whether weight loss influences reduction of LVMi in treated, obese, hypertensive patients. METHODS AND RESULTS: From the Campania Salute Network registry, we identified 1546 obese hypertensive patients (50 ± 9 years, 43% women) with more than 12 months follow-up. Echocardiographic reduction of LVMi was considered as achievement of normal values (<47 g/m2.7 in women or <50 g/m2.7 in men) or a reduction of ≥10% during follow-up. Weight loss was considered as ≥5% reduction in body weight, and occurred in 403 patients (26%) during a median follow-up of 50 months (IQrange:31-93). Median weight loss was 8.6% (IQrange:6.5-12). Patients with weight loss had higher baseline body mass index (p < 0.05), while there was no difference in age, sex, duration of hypertension, prevalence of diabetes, metabolic syndrome and average blood pressure during follow-up. During follow-up, 152 patients (9.8%) exhibited reduction of LVMi. Reduction of LVMi was more frequent (12.9% vs 9.1%, p < 0.030) in patients losing weight than in those who did not. In logistic regression analysis, weight loss was associated with reduction of left ventricular mass index (OR 1.51 [95%CI 1.02-2.23], p = 0.039), independent of significant associations with younger age, lower average systolic blood pressure during follow-up, longer follow-up time and higher LVMi at baseline. CONCLUSION: In treated obese hypertensive patients, weight loss during follow-up promotes significant reduction of LVMi, independent of baseline characteristics and blood pressure control.

Is increased uric acid a risk factor or a defensive response? The Campania Salute Network.

BACKGROUND AND AIMS: Circulating uric acid (UA) is positively associated with body mass index (BMI), blood glucose, blood pressure (BP), markers of inflammation, and altered lipid profile. UA has also anti-oxidative properties which might be beneficial for cardiovascular (CV) system. It is still debated whether or not UA is independently associated with increased CV morbidity and/or mortality. METHODS AND RESULTS: We studied prognostic impact of UA in 8833 hypertensive adults (mean age 53 ± 12 yrs, 3857 women) from the Campania Salute Network, without prevalent CV disease and more than stage 3 CKD. We calculated standardized UA Z-score, adjusted for age, sex, glomerular filtration rate, and BMI. Low and high UA and UA Z-score quartiles were compared to the 2 middle quartiles assumed to be "normal". Prevalence of obesity and diabetes was higher in low and high than in normal UA Z-score group (all p < 0.001). Systolic BP, left ventricular mass, carotid intima thickness were significantly higher and ejection fraction was reduced in the presence of high UA Z-score (all p < 0.001). Over 33-months average follow-up, incident major CV end-points (MACE) were not significantly different among low, normal and high UA or UA Z-score. In the latter analysis, however, incident MACE tended to be more frequent in the low than the high UA Z-score. Despite the results of multivariable analyses, the effect of less aggressive therapy in low UA Z-score cannot be excluded with certainty. CONCLUSION: In treated hypertensive patients, high levels of UA normalized for major biological determinants do not independently predict CV outcome. CLINICALTRIALS. GOV IDENTIFIER: NCT02211365.

Interferon-γ release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-analysis.

We conducted a systematic review and meta-analysis to compare the accuracy of the QuantiFERON-TB® Gold In-Tube (QFT-G-IT) and the T-SPOT®.TB assays with the tuberculin skin test (TST) for the diagnosis of latent Mycobacterium tuberculosis infection (LTBI). The Medline, Embase and Cochrane databases were explored for relevant articles in November 2009. Specificities, and negative (NPV) and positive (PPV) predictive values of interferon-γ release assays (IGRAs) and the TST, and the exposure gradient influences on test results among bacille Calmette-Guérin (BCG) vaccinees were evaluated. Specificity of IGRAs varied 98-100%. In immunocompetent adults, NPV for progression to tuberculosis within 2 yrs were 97.8% for T-SPOT®.TB and 99.8% for QFT-G-IT. When test performance of an immunodiagnostic test was not restricted to prior positivity of another test, progression rates to tuberculosis among IGRA-positive individuals followed for 19-24 months varied 8-15%, exceeding those reported for the TST (2-3%). In multivariate analyses, the odd ratios for TST positivity following BCG vaccination varied 3-25, whereas IGRA results remained uninfluenced and IGRA positivity was clearly associated with exposure to contagious tuberculosis cases. IGRAs may have a relative advantage over the TST in detecting LTBI and allow the exclusion of M. tuberculosis infection with higher reliability.

Role of the quantiferon-TB test in ruling out pleural tuberculosis: a multi-centre study.

Diagnosing pleural tuberculosis (plTB) might be difficult due to limited sensitivity of conventional microbiology tools. As M. tuberculosis (MTB)-specific T cells are recruited into pleural space in plTB, their detection may provide useful clinical information. To this aim, in addition to standard diagnostic tests, we used the QuantiFERON-TB Gold In-Tube (QFT-IT) test in blood and pleural effusion (PE) samples from 48 patients with clinical suspicion of plTB, 18 (37.5%) of whom had confirmed plTB. Four of them (22.2%) tested positive with a nucleic acid amplification test for MTB. The tuberculin skin test was positive in most confirmed plTB cases (88.9%). Positive QFT-IT tests were significantly more frequent in patients with confirmed plTB, as compared to patients with an alternative diagnosis, both in blood (77.7 vs 36.6%, p=0.006) and in PE samples (83.3% vs 46.6%, p=0.02). In addition, both blood and PE MTB-stimulated IFN-gamma levels were significantly higher in plTB patients (p=0.03 and p=0.0049 vs non-plTB, respectively). In blood samples, QFT-IT had 77.8% sensitivity and 63.3% specificity, resulting in 56.0% positive (PPV) and 82.6% negative (NPV) predictive values. On PE, QFT-IT sensitivity was 83.3% and specificity 53.3% (PPV 51.7% and NPV 84.2%). The optimal AUC-derived cut-off for MTB-stimulated pleural IFN-gamma level was 3.01 IU/mL (77.8% sensitivity, 80% specificity, PPV 68.4% and NPV 82.8%). These data suggest that QFT-IT might have a role in ruling out plTB in clinical practice.

Endogenous blood maximal interferon-gamma production may predict response to interferon-gamma 1beta treatment in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an untreatable lung disorder with a mean survival of 3 years after diagnosis. Treatment with interferon-gamma (IFN-gamma) 1beta has been reported to significantly improve lung function and arterial oxygen saturation in a first randomized controlled trial; unexpectedly, these findings have not been confirmed in a subsequent large placebo-controlled randomized study. Another larger placebo-controlled randomized trial has been stopped because data analyzed at interim analysis excluded the possibility that treatment with IFN-gamma 1beta would cause a significant reduction in the risk of death. METHODS: Seven Italian male patients diagnosed with IPF were treated with IFN-gamma 1beta (200 microg/die subcutaneously three times a week), accordingly to the indications of the Italian Drug Agency. Based on available studies the response to treatment was pre-defined as changes in either lung function (FVC and DLCO) or oxygen arterial saturation. All patients consented to provide a peripheral blood sample for endogenous IFN-gamma production measurement with the ELISpot assay before treatment and 6 months thereafter. RESULTS: Four of 7 patients improved or stabilized their lung function after 6 months treatment. Using the ELISpot assay to quantify the maximal production of endogenous IFN-gamma on peripheral blood samples, these 4 patients had a significantly higher endogenous IFN-gamma production before therapy, as compared to the 3 patients who deteriorated (91.3 +/- 49.6 vs. 277.8 +/- 34.2 spot forming cells, p = 0.023). No significant differences were observed after 6 months of treatment. DISCUSSION: These preliminary results suggest that some IPF patients might benefit from treatment with IFN-gamma 1beta and may help to interpret the results of large randomized trials, suggesting that individual susceptibility could determine clinical response to treatment.

Interferon-gamma-release assays detect recent tuberculosis re-infection in elderly contacts.

The tuberculin skin test (TST) does not discriminate between recent and remote latent tuberculosis infection (LTBI). This study was carried out to test two interferon-gamma-based blood assays in recent contacts with high prevalence of remote LTBI. We performed a contact tracing investigation in a nursing home for the elderly, where elderly patients were exposed to a case of pulmonary tuberculosis. TST, QuantiFERON-TB Gold (QFT-G) and T-SPOT.TB (TS.TB) were performed 8 weeks after the end of potential exposure. IFN-gamma measurements were recorded and correlation with exposure was evaluated. Twenty-seven (37.5%), 32 (44.4%) and 16 (22.2%) subjects were TST, TS.TB and QFT-G positive, respectively; agreement between TS.TB and QFT-G was good among exposed subjects only (K=0.915, 0.218 in unexposed, p<0.001). When amounts of IFN-gamma were corrected for the number of producing T cells, specific IFN-gamma production was significantly different between exposed and unexposed individuals (16.75+/-5.40 vs 2.33+/-0.71 IFN-gamma IU/1000 SFC, p=0.0001). QFT-G and TS.TB provided discordant results among elderly contacts. Unlike TST, the specific IFN-gamma response might discriminate between recent and long-lasting tuberculosis infection.

Evaluation of the left ventricular anatomy in hypertrophic cardiomyopathy: comparison between echocardiography and cardiac magnetic resonance imaging.

AIM: The aim of this study was to assess the relationship between echocardiographic indexes of left ventricular (LV) hypertrophy with LV mass (LVM) obtained at cardiac magnetic resonance (CMR) in a population of patients with hypertrophic cardiomiopathy (HCM). METHODS: Thirty-nine patients with HCM underwent echocardiography and CMR. By echocardiography maximal wall thickness (MWT), Spirito' and Maron's hypertrophy index and the Wigle's score were obtained. Absolute LVM was measured through CMR and indexed to body surface area (LVMi). Data were analysed using linear regression analysis. RESULTS: In 31% of patients there was an incomplete echocardiographic LV anatomic characterization. However, there was a good correlation between MWT measured at echocardiography and at CMR (P<0.001; r=0.755). Overall echocardiographic indexes of LV hypertrophy correlate with either LVM and LVMi: MWT (P=0.008, r=0.420 and P=0.003, r=0.467, respectively); Spirito' and Maron's hypertrophy index (P=0.003, r=0.551 and P=0.001, r=0.606, respectively) and Wigle's score (P=0.004, r=0.522 and P=0.004, r=0.522, respectively). CONCLUSION: In our HCM population, although a complete anatomic LV anatomic characterization was not obtained by echocardiography in all patients, echocardiographic hypertrophic indexes showed a good correlation with LVM obtained by CMR.

Pathogenesis of hypertrophic cardiomyopathy. Impact of growth factors on left ventricular anatomy.

AIM: The aim of this study was to evaluate the effect of insulin-like growth factor 1 (IGF1) and transforming growth factor beta-1 (TGFbeta-1) on collagen turnover, left ventricular (LV) hypertrophy and on passive diastolic function of the LV in hypertrophic cardiomyopathy (HCM). METHODS: This study group comprised 34 patients with non-dilated HCM. Procollagen I amino-terminal propeptide (PINP) and collagen I carboxy-terminal telopeptide (ICTP) were measured by radioimmunoassay. Matrix metalloproteinase 9 (MMP 9), IGF1 and TGFalfa-1 were determined by enzyme-linked immunosorbent assay. The difference in duration between transmitral forward (A) and pulmonary venous retrograde (Ar) waves, was considered as an estimate of passive diastolic function; the ratio between the peak flow velocity at rapid filling at the mitral level (E) and E' measured by tissue Doppler was considered an estimate of active diastolic function. LV mass was measured and normalized to body surface area (LVMi) by cardiac magnetic resonance imaging. RESULTS: LVMi correlates to E/E' (r=0.597, P=0.019 ) and is inversely related to A-Ar (r=0.453, P=0.015). TGFbeta-1 is directly related to active MMP 9 (r=0.439, P=0.012 ). IGF1 is directly related to PICP-ICTP (r=0.347, P=0.501), that expresses the balance between collagen I synthesis and its degradation. CONCLUSION: The study demonstrated that in HCM, LVMi influences active and passive diastolic dysfunction and that IGF1 stimulates collagen synthesis and TGFbeta-1 is related to LV hypertrophy.

Effect of diabetes and metabolic syndrome on myocardial mechano-energetic efficiency in hypertensive patients. The Campania Salute Network.

Reduced myocardial mechano-energetic efficiency (MEE), estimated as stroke volume/heart rate ratio per g of left ventricular (LV) mass (LVM), and expressed in µl s-1 g-1 (MEEi), is a strong predictor of cardiovascular (CV) events, independently of LV hypertrophy and other confounders, including type II diabetes (DM). Decreased MEEi is more frequent in patients with diabetes. In the present analysis we evaluated the interrelation among MEEi, DM and metabolic syndrome (MetS) in the setting of arterial hypertension. Hypertensive patients from the Campania Salute Network, free of prevalent CV disease and with ejection fraction >50% (n=12 503), were analysed. Coexistence of MetS and DM was ordinally categorized into 4 groups: 8235 patients with neither MetS nor DM (MetS-/DM-); 502 without MetS and with DM (MetS-/DM+); 3045 with MetS and without DM (MetS+/DM-); and 721 with MetS and DM (MetS+/DM+). After controlling for sex, systolic blood pressure, body mass index, relative wall thickness (RWT), antihypertensive medications and type of antidiabetic therapy, MEEi was 333 µl s-1 g-1 in MetS-/DM-, 328 in MetS-/DM+, 326 in MetS+/DM- and 319 in MetS+/DM+ (P for trend <0.0001). In pairwise comparisons (Sidak-adjusted), all conditions, except MetS-/DM+, were significantly different from MetS-/DM- (all P<0.02). No statistical difference was detected between MetS-/DM+ and MetS+/DM-. Both MetS and DM are associated with decreased MEEi in hypertensive patients, independently to each other, but the reduction is statistically less evident for MetS-/DM+. MetS+/DM+ patients have the lowest levels of MEEi, consistent with the alterations of energy supply associated with the combination of insulin resistance with insulin deficiency.

Macrolides in the treatment of asthma and cystic fibrosis.

Asthma and cystic fibrosis are two respiratory diseases characterized by chronic inflammation, leading to remodelling of the airways. Macrolides are widely used antibiotics, with a peculiar anti-inflammatory effect. On the basis of the methodologies used by the Cochrane collaboration, this review discusses the evidence for their long-term use as anti-inflammatory agents in these two diseases. Three randomized-controlled trials (RCTs) were identified for both asthma and cystic fibrosis. A positive effect of macrolides on reducing eosinophil numbers and markers of eosinophilic inflammation was demonstrated in patients with asthma. Data on cystic fibrosis demonstrated an effect on lung function with an increase of 5.4% in forced vital capacity (FVC) in patients treated with macrolide vs. placebo, but without a significant effect on FEV1. Side-effects were rare, mild and reversible on withdrawal of treatment. Although preliminary data from small studies are promising, the role of macrolides in the treatment of these chronic disorders needs to be more firmly established with larger, well-designed trials, targeted to investigate major clinical outcomes.

Exercise capacity in hypertrophic cardiomyopathy depends on left ventricular diastolic function.

Some studies have demonstrated that left ventricular (LV) diastolic function is the principal determinant of impaired exercise capacity in hypertrophic cardiomyopathy (HC). In this study we sought the capability of echocardiographic indexes of diastolic function in predicting exercise capacity in patients with HC. We studied 52 patients with HC while they were not on drugs;12 of them had LV tract obstruction at rest. Diastolic function was assessed by M-mode and Doppler echocardiography by measuring: (1) left atrial fractional shortening, and the slope of posterior aortic wall displacement during early atrial emptying on M-mode left atrial tracing; and (2) Doppler-derived transmitral and pulmonary venous flow velocity indexes. Exercise capacity was assessed by maximum oxygen consumption by cardiopulmonary test during cycloergometer upright exercise. Maximum oxygen consumption correlated with the left atrial fractional shortening (r = 0.63, p <0.001), the slope of posterior aortic wall displacement during early atrial emptying (r = 0.55, p <0.001), age (r = -0.50; p <0.001), pulmonary venous diastolic anterograde velocity (r = 0.41, p <0.01), and the systolic filling fraction (r = -0.43; p <0.01). By stepwise multiple linear regression analysis, left atrial fractional shortening and the pulmonary venous systolic filling fraction were the only determinants of the maximum oxygen consumption (multiple r = 0.70; p <0.001). Exercise capacity did not correlate with Doppler-derived transmitral indexes. Thus, in patients with HC, exercise capacity was determined by passive LV diastolic function, as assessed by the left atrial M-mode and Doppler-derived pulmonary venous flow velocities.

Influence of left ventricular cavity size on clinical presentation in hypertrophic cardiomyopathy.

The aim of this study was to assess whether left ventricular (LV) cavity size relates to functional impairment and syncope in patients with hypertrophic cardiomyopathy (HC). LV diastolic dysfunction influences functional limitation in HC. A reduced LV end-diastolic dimension may underlie impaired diastolic properties and be implicated in hemodynamic syncope. Eighty-two consecutive patients with HC (off drugs, in sinus rhythm) underwent echocardiography to measure LV end-diastolic dimension in the short-axis view (indexed to the body surface area) and radionuclide angiography (n = 50) to calculate peak filling rate (normalized to stroke counts/s). Patients in New York Heart Association functional classes II to IV had smaller LV end-diastolic dimension (23.2 +/- 2.6 vs 25.5 +/- 2.5 mm/M2, p = 0.0001) and lower peak filling rate (4.3 +/- 1.4 vs 5.1 +/- 1.3 stroke counts/s, p = 0.036) than those in New York Heart Association class I. LV end-diastolic diameter was correlated to peak filling rate (r = 0.37; p = 0.008). The most potent predictors of functional limitation were LV end-diastolic dimension (relative risk [RR] 0.63, confidence interval [CI] 0.45 to 0.88; p = 0.008), age (RR 1.09, CI 1.03 to 1.17; p = 0.003), and LV thickness score (RR 1.08, CI 1.02 to 1.13; p = 0.003). LV cavity size was smaller in patients with functional limitation irrespective of obstruction and hypertrophy. Patients with differed from those without a history of syncope for a smaller LV end-diastolic dimension (23.2 +/- 2.5 vs 25.0 +/- 2.7 mm/M2, p = 0.008), which was the only independent predictor of syncope (RR 0.77, CI 0.63 to 0.95; p = 0.013). Thus, a small LV cavity size is associated with functional limitation and history of syncope in HC.

Noninvasive evaluation of left ventricular diastolic function in hypertrophic cardiomyopathy.

Diastolic dysfunction is common in hypertrophic cardiomyopathy (HC). Previous studies suggest that Doppler transmitral flow velocity profiles, and the left atrial (LA) M-mode echogram can be used noninvasively to evaluate left ventricular (LV) diastolic function. However, this has not been proved in HC. In this study we determined the relation of Doppler transmitral flow velocity profiles and the LA M-mode echograms to invasive indexes of LV diastolic function in patients with HC. We studied 25 patients with HC, while off drugs, and calculated LA global and active fractional shortening and the slope of both early and late displacement of the posterior aortic wall during LA emptying by M-mode echocardiography. We calculated peak velocity of early (E) and atrial (A) filling, E to A ratio, and E-wave deceleration time by pulsed Doppler echocardiography, and simultaneous radionuclide angiography, LV pressures, time constant of isovolumic relaxation tau, and the constant of chamber stiffness k by cardiac catheterization. The time constant of isovolumic relaxation tau correlated with the slope of early posterior aortic wall displacement (r = 0.59; p <0.01). LV end-diastolic pressure correlated with global LA fractional shortening (r = -0.75; p <0.001); the constant of chamber stiffness k correlated with active LA fractional shortening (r = -0.53; p <0.02). In a subset of 13 patients, in whom echocardiography and cardiac catheterization were performed simultaneously, similar results were found. LA M-mode recordings provide a more reliable noninvasive assessment of diastolic function in HC than mitral Doppler indexes.

Effects of dual-chamber pacing in hypertrophic cardiomyopathy on left ventricular outflow tract obstruction and on diastolic function.

Hypertrophic cardiomyopathy (HC) is characterized by impaired diastolic function and, in about 1/4 of patients, left ventricular (LV) outflow tract obstruction. Atrioventricular (AV) pacing diminishes LV outflow tract gradient in HC, but impairs diastolic function in the experimental animal and in different categories of patients. To investigate the effects of AV pacing on hemodynamics and LV function in obstructive HC, 16 patients with HC were studied by cardiac catheterization and simultaneous radionuclide angiography during atrial and AV pacing. The resting LV outflow tract gradient decreased with AV pacing from 60 +/- 34 to 38 +/- 37 mm Hg (mean +/- SD; p <0.001). Regional ejection fraction decreased significantly at the septal level from 0.81 +/- 0.21% to 0.69 +/- 0.27% (p <0.01). Pulmonary artery wedge pressure increased from 10 +/- 5 to 15 +/- 6 mm Hg (p <0.001). AV pacing induced asynchrony (i.e., the coefficient of variation of the time to end-systole increased from 7 +/- 4% to 14 +/- 10% (p <0.01). The time constant of isovolumetric relaxation (t) increased from 58 +/- 24 to 74 +/- 33 ms (p <0.02), and peak filling rate decreased from 491 +/- 221 to 416 +/- 184 ml/s (p <0.05). Thus, AV pacing greatly diminishes resting obstruction through a reduction in septal ejection fraction (i.e., an increase in LV outflow tract width in systole), but impairs active diastolic function and increases filling pressures. These latter effects are potentially detrimental in patients with HC in whom diastolic dysfunction is present.

Effects of diltiazem on left ventricular systolic and diastolic function in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HC) is characterized by impaired diastolic function, and left ventricular (LV) outflow tract obstruction in about one-fourth of patients. Verapamil improves diastolic properties, but may have dangerous adverse effects. This study investigates the effects of diltiazem on hemodynamics and LV function in 16 patients with HC who were studied with cardiac catheterization and simultaneous radionuclide angiography. Studies were performed during atrial pacing (15 beats above spontaneous rhythm) at baseline and during intravenous diltiazem administration (0.25 mg x kg(-1) over 2 minutes, and 0.014 mg x kg(-1) x min(-1). Diltiazem induced a systemic vasodilation (cardiac index: 3.4 +/- 1.0 to 4.0 +/- 1.0 L x min(-1) x m(-2), p = 0.003; aortic systolic pressure: 116 +/- 16 to 107 +/- 19 mm Hg, p = 0.007; systemic resistance index: 676 +/- 235 to 532 +/- 193 dynes x s x cm(-5) x m(-2), p = 0.006), not associated with changes in the LV outflow tract gradient. The end-systolic pressure/volume ratio decreased (30 +/- 42 to 21 +/- 29 mm Hg x ml(-1) x m(-2); p = 0.044). Pulmonary artery wedge pressure (11 +/- 5 to 15 +/- 6 mm Hg, p = 0.006), and peak filling rate increased (4.1 +/- 1.3 to 6.0 +/- 2.4 stroke counts x s(-1), p = 0.004). The time constant of isovolumetric relaxation tau decreased (74 +/- 40 to 59 +/- 38 ms, p = 0.045). The constant of LV chamber stiffness did not change. Thus, active diastolic function is improved by the acute administration of diltiazem by both direct action and changes in hemodynamics and loading conditions. LV outflow tract gradient does not increase despite systemic vasodilation. In some patients, however, a marked increase in obstruction and a potentially harmful elevation in pulmonary artery wedge pressure do occur. Passive diastolic function is not affected.

Synthesis and physicochemical characterization of a new material (PUPA) based on polyurethane and poly(amido-amine) components capable of strongly adsorbing quantities of heparin.

The synthesis of new materials (PUPAs) based on a commercial polyurethane and a heparin-complexing polymer, poly(amido-amine), was studied. PUPAs are capable of adsorbing heparin because the basic nitrogens of poly(amido-amine), once protonated, interact with the negative charges carried by the heparin molecule. Six different samples of PUPA were synthesized having a varied ratio of the components. The quantity of basic nitrogen on the surface and the bound heparin for each sample was determined. Two different kinds of heparin are present on a PUPA surface: one is strongly bound but can be detached by 0.1 M NaOH solution, the other is physically adsorbed and is slowly released by a stream of saline solution. A relationship between the quantity of strongly bound heparin and basic nitrogen was found. SEM and FTIR-ATR analysis were performed on all the PUPA samples. The mechanical characteristics change according to chemical composition.

Multi-centre clinical investigation of indapamide in the United States: a review.

Indapamide, a new indoline antihypertensive agent, has been the subject of a worldwide programme to develop this drug for general clinical use. The results are described of the multi-centre U.S. clinical programme demonstrating the effectiveness and tolerance of indapamide for the treatment of hypertension. All work was conducted under U.S. Federal Food and Drug Administration guidelines, and resulted recently in a New Drug Application. A total of 1891 subjects or patients participated in 27 separate studies conducted by 91 investigators. In controlled clinical trials comparing 2.5 mg indapamide once daily with 50 mg hydrochlorothiazide once daily for 40 weeks in patients with mild to moderate essential hypertension, indapamide produced a reduction of supine blood pressure of -9.5/-14.3 mmHg as compared with -7.6/-11.4 mmHg for hydrochlorothiazide. In combination with methyldopa, propranolol, clonidine, guanethidine and hydralazine, indapamide consistently produced a greater decrease in arterial pressure than did those agents given alone. Indapamide added to these step-care agents did not result in a meaningful increase in adverse reactions. Indapamide has been the subject of a long-term safety study in which over 100 hypertensive patients have been followed up for 2 years or longer. During this period of time, indapamide was well tolerated and remained effective. No biochemical, electrocardiographic or ophthalmological changes were associated with its use. Other studies with indapamide are discussed describing the systemic and renal haemodynamic effects, pharmacokinetic properties and special safety studies conducted with this agent. The use of indapamide in patients with hepatic or renal impairment is reviewed in detail.

Environmental biochemistry of chromium.

Chromium is a d-block transitional element with many industrial uses. It occurs naturally in various crustal materials and is discharged to the environment as industrial waste. Although it can occur in a number of oxidation states, only 3+ and 6+ are found in environmental systems. The environmental behavior of Cr is largely a function of its oxidation state. Hexavalent Cr compounds (mainly chromates and dichromates) are considered toxic to a variety of terrestrial and aquatic organisms and are mobile in soil/water systems, much more so than trivalent Cr compounds. This is largely because of differing chemical properties: Hexavalent Cr compounds are strong oxidizers and highly soluble, while trivalent Cr compounds tend to form relatively inert precipitates at near-neutral pH. The trivalent state is generally considered to be the stable form in equilibrium with most soil/water systems. A diagram of the Cr cycle in soils and water is given in Fig. 6 (Bartlett 1991). This illustration provides a summary of environmentally relevant reactions. Beginning with hexavalent Cr that is released into the environment as industrial waste, there are a number of possible fates, including pollution of soil and surface water and leaching into groundwater, where it may remain stable and, in turn, can be taken up by plants or animals, and adsorption/precipitation, involving soil colloids and/or organic matter. Herein lies much of the environmental concern associated with the hexavalent form. A portion of the Cr(VI) will be reduced to the trivalent form by inorganic electron donors, such as Fe2+ and S2-, or by bioprocesses involving organic matter. Following this conversion, Cr3+ can be expected to precipitate as oxides and hydroxides or to form complexes with numerous ligands. This fraction includes a vast majority of global Cr reserves. Soluble Cr3+ complexes, such as those formed with citrate, can undergo oxidation when they come in contact with manganese dioxide, thus reforming hexavalent Cr. In trace amounts, Cr is an essential component of animal nutrition, functioning mainly in glucose metabolism, and possibly in fat metabolism. While shown to be nonessential for plants, it is required by some microbes, possibly as a cofactor for specific enzyme systems. Bacteria with plasmid-conferred resistance to Cr(VI) have been isolated from water, soil, and sediments, and the resistance mechanisms have been somewhat characterized. One of the chief mechanisms is bioreduction of toxic Cr(VI) to the relatively nontoxic Cr(III). This has been shown to occur directly, by enzymatic processes at the cell membrane, and indirectly, with microbially produced H2S acting as the reductant.(ABSTRACT TRUNCATED AT 400 WORDS)

Recombinant tissue-type plasminogen activator therapy in prosthetic mitral valve thrombosis: assessment by transthoracic and transesophageal echocardiography.

Prosthetic cardiac thrombosis is a life-threatening complication that needs prompt diagnosis and therapy. We used recombinant tissue-type plasminogen activator (rT-PA), followed by heparin, in three patients with mitral prosthetic thrombosis, which was evident in two and suspect in one. Transthoracic and transesophageal echocardiography were employed in the diagnosis of both thrombosis and its resolution. No complications occurred. Immediately after the end of treatment with rT-PA, clinical status and echocardiographic data improved in all cases: transthoracic echocardiography showed the normalization of prosthetic function and transesophageal echocardiography showed resolution of thrombosis. One patient needed reoperation for rethrombosis due to the presence of prosthetic fibrous clot. rT-PA, followed by heparin, led to a good clinical result without bleeding and embolic complications in selected patients with mitral prosthetic thrombosis. Transthoracic and transesophageal echocardiography are complementary diagnostic tools in the diagnosis and management of patients with prosthetic thrombosis.

Mid-term results of the valve-on-valve technique for bioprosthetic failure.

OBJECTIVE: Redo operations for bioprosthesis malfunction can sometimes be technically very demanding and cardiac structures may be damaged. Excising only the leaflets of the damaged bioprosthesis and leaving the old ring in situ on which the 'new' mechanical valve is sutured can, in very selected cases, represent a solution. METHODS: Twenty-two patients were operated on, with the valve-on-valve technique, from September 1991 through December 1992. There were three operative deaths. RESULTS: The surviving 19 patients were followed-up from 83 to 98 months (mean 90.5 months.). There were two late deaths. The patients were examined clinically and with transthoracic and transesophageal echocardiograms. All patients were in good condition and the echocardiographic examinations showed no clinically important gradients across the prostheses. CONCLUSIONS: The valve-on-valve technique, in certain difficult situations, can give successful mid-term results.