Urinary hyaluronidase activity is closely related to vasopressinergic system following an oral water load in men: a potential role in blood pressure regulation and early stages of hypertension development.

Introduction: Blood pressure (BP) regulation is a complex process involving several factors, among which water-sodium balance holds a prominent place. Arginin-vasopressin (AVP), a key player in water metabolism, has been evoked in hypertension development since the 1980s, but, to date, the matter is still controversial. Hyaluronic acid metabolism has been reported to be involved in renal water management, and AVP appears to increase hyaluronidase activity resulting in decreased high-molecular-weight hyaluronan content in the renal interstitium, facilitating water reabsorption in collecting ducts. Hence, our aim was to evaluate urinary hyaluronidase activity in response to an oral water load in hypertensive patients (HT, n=21) compared to normotensive subjects with (NT+, n=36) and without (NT-, n=29) a family history of hypertension, and to study its association with BP and AVP system activation, expressed by serum copeptin levels and urine Aquaporin 2 (AQP2)/creatinine ratio. Methods: Eighty-six Caucasian men were studied. Water load test consisted in oral administration of 15-20 ml of water/kg body weight over 40-45 min. BP, heart rate, serum copeptin, urine hyaluronidase activity and AQP2 were monitored for 4 hours. Results: In response to water drinking, BP raised in all groups with a peak at 20-40 min. Baseline levels of serum copeptin, urinary hyaluronidase activity and AQP2/creatinine ratio were similar among groups and all decreased after water load, reaching their nadir at 120 min and then gradually recovering to baseline values. Significantly, a blunted reduction in serum copeptin, urinary hyaluronidase activity and AQP2/creatinine ratio was observed in NT+ compared to NT- subjects. A strong positive correlation was also found between urinary hyaluronidase activity and AQP2/creatinine ratio, and, although limited to the NT- group, both parameters were positively associated with systolic BP. Discussion: Our results demonstrate for the first time the existence in men of a close association between urinary hyaluronidase activity and vasopressinergic system and suggest that NT+ subjects have a reduced ability to respond to water loading possibly contributing to the blood volume expansion involved in early-stage hypertension. Considering these data, AVP could play a central role in BP regulation by affecting water metabolism through both hyaluronidase activity and AQP2 channel expression.

Why the 2022 Po River drought is the worst in the past two centuries.

The causes of recent hydrological droughts and their future evolution under a changing climate are still poorly understood. Banking on a 216-year river flow time series at the Po River outlet, we show that the 2022 hydrological drought is the worst event (30% lower than the second worst, with a six-century return period), part of an increasing trend in severe drought occurrence. The decline in summer river flows (-4.14 cubic meters per second per year), which is more relevant than the precipitation decline, is attributed to a combination of changes in the precipitation regime, resulting in a decline of snow fraction (-0.6% per year) and snowmelt (-0.18 millimeters per day per year), and to increasing evaporation rate (+0.013 cubic kilometers per year) and irrigated areas (100% increment from 1900). Our study presents a compelling case where the hydrological impact of climate change is exacerbated by local changes in hydrologic seasonality and water use.

Changing climate both increases and decreases European river floods.

Climate change has led to concerns about increasing river floods resulting from the greater water-holding capacity of a warmer atmosphere1. These concerns are reinforced by evidence of increasing economic losses associated with flooding in many parts of the world, including Europe2. Any changes in river floods would have lasting implications for the design of flood protection measures and flood risk zoning. However, existing studies have been unable to identify a consistent continental-scale climatic-change signal in flood discharge observations in Europe3, because of the limited spatial coverage and number of hydrometric stations. Here we demonstrate clear regional patterns of both increases and decreases in observed river flood discharges in the past five decades in Europe, which are manifestations of a changing climate. Our results-arising from the most complete database of European flooding so far-suggest that: increasing autumn and winter rainfall has resulted in increasing floods in northwestern Europe; decreasing precipitation and increasing evaporation have led to decreasing floods in medium and large catchments in southern Europe; and decreasing snow cover and snowmelt, resulting from warmer temperatures, have led to decreasing floods in eastern Europe. Regional flood discharge trends in Europe range from an increase of about 11 per cent per decade to a decrease of 23 per cent. Notwithstanding the spatial and temporal heterogeneity of the observational record, the flood changes identified here are broadly consistent with climate model projections for the next century4,5, suggesting that climate-driven changes are already happening and supporting calls for the consideration of climate change in flood risk management.

Changing climate shifts timing of European floods.

A warming climate is expected to have an impact on the magnitude and timing of river floods; however, no consistent large-scale climate change signal in observed flood magnitudes has been identified so far. We analyzed the timing of river floods in Europe over the past five decades, using a pan-European database from 4262 observational hydrometric stations, and found clear patterns of change in flood timing. Warmer temperatures have led to earlier spring snowmelt floods throughout northeastern Europe; delayed winter storms associated with polar warming have led to later winter floods around the North Sea and some sectors of the Mediterranean coast; and earlier soil moisture maxima have led to earlier winter floods in western Europe. Our results highlight the existence of a clear climate signal in flood observations at the continental scale.

Calcium channel blockade blunts the renal effects of acute nitric oxide synthase inhibition in healthy humans.

Our aim was to investigate whether blockade of calcium channels (CCs) or angiotensin II type 1 receptors (AT1R) modulates renal responses to nitric oxide synthesis inhibition (NOSI) in humans. Fourteen sodium-replete, healthy volunteers underwent 90-min infusions of 3.0 µg·kg-1·min-1 NG-nitro-l-arginine methyl ester (l-NAME) on 3 occasions, preceded by 3 days of either placebo (PL), 10 mg of manidipine (MANI), or 50 mg of losartan (LOS). At each phase, mean arterial pressure (MAP), glomerular filtration rate (GFR; inulin), renal blood flow (RBF; p-aminohippurate), urinary sodium (UNaV), and 8-isoprostane (U8-iso-PGF2αV; an oxidative stress marker) were measured. With PL + l -NAME, the following changes were observed: +6% MAP (P < 0.005 vs. baseline), -10% GFR, -20% RBF, -49% UNaV (P < 0.001), and +120% U8-iso-PGF2αV (P < 0.01). In contrast, MAP did not increase during LOS + l-NAME or MANI + l-NAME (P > 0.05 vs. baseline), whereas renal changes were the same during LOS + l-NAME vs. PL + l-NAME (ANOVA, P > 0.05). However, during MANI + l-NAME, changes vs. baseline in GFR (-6%), RBF (-12%), and UNaV (-34%) were blunted vs. PL + l-NAME and LOS + l-NAME (P < 0.005), and the rise in U8-iso-PGF2αV was almost abolished (+37%, P > 0.05 vs. baseline; P < 0.01 vs. PL + l-NAME or LOS + l-NAME). We conclude that, since MANI blunted l-NAME-induced renal hemodynamic changes, CCs participate in the renal responses to NOSI in healthy, sodium-replete humans independent of changes in MAP and without the apparent contribution of the AT1R. Because the rise in U8-iso-PGF2αV was essentially prevented during MANI + l-NAME, CC blockade may oppose the renal effects of NOSI in part by counteracting oxidative stress responses to acutely impaired renal NO bioavailability.

Sex-related differences in left ventricular structure in early adolescent non-professional athletes.

BACKGROUND: Professional athletes exhibit lower left ventricular wall thicknesses, diameters and mass (in females), with less frequent training-related electrocardiogram (ECG) changes, as compared with controls. METHODS: We studied the association of sex with left ventricular structure in trained early adolescents. Two hundred and six adolescent Caucasian athletes (mean age 13.8 ± 1.6, range 11.8-16.9 years, 158 males and 48 females), with similar degree of training underwent ECG and echocardiographic measurements of left ventricular diameters, thicknesses and mass, with relative wall thickness as the remodelling index. RESULTS: As compared with females, males exhibited greater maximal wall thickness (males = 8.7 ± 1.2 vs. females = 7.9 ± 0.8) and indexed left ventricular mass (100 ± 18 g/m(2) vs. 79 ± 12, p < 0.001), without differences in relative wall thickness (males = 0.35 ± 0.04 vs. females = 0.34 ± 0.04) and with higher prevalence of ECG-based left ventricular hypertrophy, sinus bradycardia and ST-elevation. An analysis of covariance, using age, body surface area, systolic blood pressure, heart rate and sex as the covariates, reported that sex is a strong predictor of left ventricular mass, maximal wall thickness, left ventricular diastolic diameter and ECG-based left ventricular hypertrophy. In a binary logistic regression model analysis sex, like left ventricular mass, predicted ST-trait elevation. CONCLUSIONS: Our results suggest that, in early adolescence, female athletes have lower left ventricular mass and thicknesses compared with males, without geometrical differences. Therefore, sex, independent of age, is a strong determinant of structural parameters also in early adolescent athletes. These data indicate that sex-specific parameters are needed in the pre-participation cardiovascular screening of adolescent athletes.

Low serum ferroxidase I activity is associated with mortality in heart failure and related to both peroxynitrite-induced cysteine oxidation and tyrosine nitration of ceruloplasmin.

RATIONALE: Ceruloplasmin antioxidant function is mainly related to its ferroxidase I (FeOxI) activity, which influences iron-dependent oxidative and nitrosative radical species generation. Peroxynitrite, whose production is increased in heart failure (HF), can affect ceruloplasmin antioxidant function through amino acid modification. OBJECTIVE: We investigated the relationship between FeOxI and ceruloplasmin tyrosine and cysteine modification and explored in a cohort of patients with HF the potential clinical relevance of serum FeOxI. METHODS AND RESULTS: In patients with chronic HF (n=96, 76 ± 9 years; New York Heart Association class, 2.9 ± 0.8) and age-matched controls (n=35), serum FeOxI, FeOxII, ceruloplasmin, nitrotyrosine-bound ceruloplasmin, B-type natriuretic peptide, norepinephrine, and high-sensitivity C-reactive protein were measured, and the patients were followed up for 24 months. Ceruloplasmin, B-type natriuretic peptide, norepinephrine, and high-sensitivity C-reactive protein were increased in HF versus controls. FeOxI was decreased in HF (-20%) and inversely related to nitrotyrosine-bound ceruloplasmin (r, -0.305; P=0.003). In HF, FeOxI lower tertile had a mortality rate doubled compared with middle-higher tertiles. FeOxI emerged as a mortality predictor (hazard ratio, 2.95; 95% confidence intervals [1.29-6.75]; P=0.011) after adjustment for age, sex, hypertension, smoking, sodium level, estimated glomerular filtration rate, and high-sensitivity C-reactive protein. In experimental settings, peroxynitrite incubation of serum samples and isolated purified ceruloplasmin reduced FeOxI activity while increasing ceruloplasmin tyrosine nitration and cysteine thiol oxidation. Reduced glutathione prevented peroxynitrite-induced FeOxI drop, tyrosine nitration, and cysteine oxidation; flavonoid(-)-epicatechin, which prevented ceruloplasmin tyrosine nitration but not cysteine oxidation, partially impeded peroxynitrite-induced FeOxI drop. CONCLUSIONS: Reduced activity of serum FeOxI is associated with ceruloplasmin nitration and reduced survival in patients with HF. Both ceruloplasmin tyrosine nitration and cysteine thiol oxidation may be operant in vivo in peroxynitrite-induced FeOxI activity inhibition.

Gender, clamped hyperglycemia and arterial stiffness in patients with uncomplicated type 1 diabetes mellitus.

BACKGROUND: Diabetes mellitus (DM) reduces female gender-mediated protection against the development of renal disease possibly through effects on hyperglycemia. Women with DM also exhibit increased arterial stiffness, which may promote renal disease progression. The mechanisms responsible for increased arterial stiffness in women and the possible role of acute changes in ambient glycemia remain unknown. METHODS: Blood pressure, augmentation index (AIx), pulse wave velocity (PWV) and circulating mediators of the renin angiotensin system and nitric oxide (cGMP) were measured in men (n = 22) and women (n = 19) with uncomplicated type 1 DM under clamped euglycemic and hyperglycemic conditions. RESULTS: At baseline, men exhibited higher levels of angiotensin II (p = 0.030) and lower cGMP levels (p = 0.004), higher systolic blood pressure (124 ± 2 versus 109 ± 2 mmHg, p < 0.0001) and pulse pressure (42 ± 2 versus 58 ± 2 beats per minute, p < 0.0001). For arterial stiffness, radial (-8.0 ± 2.6% versus +5.4 ± 3.7%, p < 0.0001) and carotid AIx (-4.7 ± 2.9 versus +12.5 ± 3.0, p < 0.0001) were lower in men versus women. In contrast, carotid-femoral PWV was similar in men and women (5.20 ± 0.30 versus 5.13 ± 0.17, respectively, p = 0.853). In response to clamped hyperglycemia, systolic blood pressure increased in women (109 ± 2 to 112 ± 2 mmHg, p = 0.005) but not men. Serum aldosterone increased and cGMP declined in women but not in men. Clamped hyperglycemia did not influence arterial stiffness in either group and radial and carotid AIx remained higher in women. CONCLUSIONS: Arterial stiffness is higher in women with type 1 DM. This effect is not dependent on the effects of clamped hyperglycemia or neurohormonal activation.

Nitric oxide-angiotensin II interactions and renal hemodynamic function in patients with uncomplicated type 1 diabetes.

The objective is to elucidate the effect of nitric oxide (NO)-renin-angiotensin system (RAS) interactions on renal hemodynamic function in uncomplicated, type 1 diabetes mellitus (DM). In 14 salt-replete, male healthy volunteers (C) and 9 male DM patients on euglycemia, glomerular filtration rate (GFR), renal blood flow (RBF), filtration fraction (FF), and sodium excretion (UNaV) were measured at baseline and during a 90-min infusion of 3.0 µg·kg⁻¹·min⁻¹ NG-nitro-L-arginine-methyl-ester (L-NAME) after 3 days of pretreatment with either placebo (PL) or 50 mg losartan (LOS). Baseline GFR, RBF, and FF were higher in DM (P < 0.005). In the C group, PL + L-NAME caused declines in GFR (101 ± 3 to 90 ± 3 ml·min⁻¹·1.73 m⁻²), RBF (931 ± 22 to 754 ± 31 ml·min⁻¹·1.73 m⁻²), and UNaV (158 ± 12 to 82 ± 18 µmol/min) and an increase in FF (0.19 ± 0.02 to 0.21 ± 02; P < 0.001), which were not influenced by LOS pretreatment (P > 0.05 for LOS + L-NAME-C vs. PL + l-NAME-C). In DM, PL + L-NAME resulted in exaggerated renal effects, with changes in GFR (128 ± 3 to 104 ± 3 ml·min⁻¹·1.73 m⁻²), RBF (1,019 ± 27 to 699 ± 34 ml·min⁻¹·1.73 m⁻²), UNaV (150 ± 13 to 39 ± 14 µmol/min), and FF (0.22 ± 0.03 to 0.26 ± 0.02) that were significantly greater vs. PL + L-NAME-C (P < 0.005). LOS pretreatment blunted GFR, RBF, FF, and UNaV responses to L-NAME in DM (P < 0.005 vs. PL + L-NAME-DM), resulting in a response profile that was similar to PL + L-NAME and LOS + L-NAME in C (P > 0.05). Renal responses to L-NAME in uncomplicated, type 1 DM are exaggerated vs. C, consistent with an upregulation of NO bioactivity. LOS, without effects in C, prevents the accentuated actions of L-NAME in DM, thus indicating an augmented role for NO-RAS interactions in renal hemodynamic function in DM.

Prealbumin improves death risk prediction of BNP-added Seattle Heart Failure Model: results from a pilot study in elderly chronic heart failure patients.

BACKGROUND: An accurate prognosis prediction represents a key element in chronic heart failure (CHF) management. Seattle Heart Failure Model (SHFM) prognostic power, a validated risk score for predicting mortality in CHF, is improved by adding B-type natriuretic peptide (BNP). We evaluated in a prospective study the incremental value of several biomarkers, linked to different biological domains, on death risk prediction of BNP-added SHFM. METHODS: Troponin I (cTnI), norepinephrine, plasma renin activity, aldosterone, high sensitivity-C reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), interleukin 2 soluble receptor, leptin, prealbumin, free malondialdehyde, and 15-F2t-isoprostane were measured in plasma from 142 consecutive ambulatory, non-diabetic stable CHF (mean NYHA-class 2.6) patients (mean age 75±8years). Calibration, discrimination, and risk reclassification of BNP-added SHFM were evaluated after individual biomarker addition. RESULTS: Individual addition of biomarkers to BNP-added SHFM did not improve death prediction, except for prealbumin (HR 0.49 CI: (0.31-0.76) p=0.002) and cTnI (HR 2.03 CI: (1.20-3.45) p=0.009). In fact, with respect to BNP-added SHFM (Harrell's C-statistic 0.702), prealbumin emerged as a stronger predictor of death showing the highest improvement in model discrimination (+0.021, p=0.033) and only a trend was observed for cTn I (+0.023, p=0.063). These biomarkers showed also the best reclassification statistic (Integrated Discrimination Improvement-IDI) at 1-year (IDI: cTnI, p=0.002; prealbumin, p=0.020), 2-years (IDI: cTnI, p=0.018; prealbumin: p=0.006) and 3-years of follow-up (IDI: cTnI p=0.024; prealbumin: p=0.012). CONCLUSIONS: Individual addition of prealbumin allows a more accurate prediction of mortality of BNP enriched SHFM in ambulatory elderly CHF suggesting its potential use in identifying those at high-risk that need nutritional surveillance.

Renal hemodynamic response to L-arginine in uncomplicated, type 1 diabetes mellitus: the role of buffering anions and tubuloglomerular feedback.

According to the "tubulocentric" hypothesis of the glomerular hyperfiltration of diabetes mellitus (DM), tubuloglomerular feedback (TGF) is the critical determinant of the related renal hemodynamic dysfunction. To examine the role of TGF in human type 1 DM, 12 salt-replete healthy (C) and 11 uncomplicated DM individuals underwent measurements of glomerular filtration rate (GFR), renal blood flow (RBF), and lithium-derived absolute "distal" sodium delivery (DDNa). Measurements were made during two 3-h infusions of 0.012 mmol·kg(-1)·min(-1) l-arginine (ARG) buffered with either equimolar HCl (ARG.HCl) or citric acid (ARG.CITR). Our hypothesis was that changes in TGF signaling would be directionally opposite ARG.HCl vs. ARG.CITR according to the effects of the ARG-buffering anion on DDNa. Similar changes in C and DM followed ARG.CITR, with declines in DDNa (-0.26 ± 0.07 mmol/min C vs. -0.31 ± 0.07 mmol/min DM) and increases in RBF (+299 ± 25 vs. +319 ± 29 ml·min(-1)·1.73 m(-2)) and GFR (+6.6 ± 0.8 vs. +11.6 ± 1.2 ml·min(-1)·1.73 m(-2)). In contrast, with ARG.HCl, DDNa rose in both groups (P = 0.001), but the response was 73% greater in DM (+1.50 ± 0.15 mmol/min C vs. +2.59 ± 0.22 mmol/min DM, P = 0.001). RBF also increased (P = 0.001, +219 ± 20 ml·min(-1)·1.73 m(-2) C, +105 ± 14 DM), but ΔRBF after ARG.HCl was lower vs. ARG.CITR in both groups (P = 0.001). After ARG.HCl, ΔRBF also was 50% lower in DM vs. C (P = 0.001) and GFR, unchanged in C, declined in DM (-7.4 ± 0.9 ml·min(-1)·1.73 m(-2), P = 0.02 vs. C). After ARG.HCl, unlike ARG.CITR, DDNa increased in C and DM, associated with less ΔRBF and ΔGFR vs. ARG.CITR. This suggests that the renal hemodynamic response to ARG is influenced substantially by the opposite actions of HCl vs. CITR on DDNa and TGF. In DM, the association of ARG.HCl-induced exaggerated ΔDDNa, blunted ΔRBF, and the decline in GFR vs. C shows an enhanced TGF dependence of renal vasodilatation to ARG, in agreement with a critical role of TGF in DM-related renal hemodynamic dysfunction.

Endothelial dysfunction and high cardiovascular risk profile in severe alcoholics improve only partially following a medium-term alcohol withdrawal.

BACKGROUND: Little is known about brachial artery flow-mediated vasodilatation (FMD) in active and medium-term withdrawing heavy alcoholics (HA). METHODS: FMD and some parameters of cardiovascular (CV) risk were measured in 29 HA (average alcohol intake 135, range 86 to 215 g per day) at baseline and after a 9 ± 7 months withdrawal and in 35 teetotalers. RESULTS: HA showed baseline impaired maximal % FMD (8.5 ± 5.4 SD vs. 14.9 ± 7.4, <0.001 vs. teetotalers), higher systolic (SBP) and diastolic (DBP) blood pressure (+24 mm Hg, <0.001; +15 mm Hg, <0.01), uric acid (5.3 ± 1.1 vs. 4.4 ± 0.8 mg/dl, <0.05), high-sensitivity C-reactive protein (hs-CRP; 2.7 ± 2.0 vs. 1.0 ± 0.9 mg/l, <0.02), endothelin-1 (ET-1, 0.88 ± 0.36 vs. 0.37 ± 0.10 pg/ml,<0.001), asymmetric dimethylarginine (ADMA, 0.50 ± 0.21 vs. 0.41 ± 0.12 µmol/l, p < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (2.3 ± 1.1 vs. 1.2 ± 0.4, <0.001), and urinary 8-isoprostane (U8-iso-PGF2α) (237.2 ± 172.4 vs. 168.5 ± 96.6 pg/mg creatinine, <0.05). After withdrawal, SBP fell by 15 mm Hg, DBP by 11 mm Hg (p < 0.001), and hs-CRP by 0.94 mg/l (p < 0.02), all remaining still higher than teetotalers (<0.05, 0.01, 0.05 respectively). ET-1, HOMA-IR, and U8-iso-PGF2α were unchanged (p = NS vs. baseline, <0.05 to 0.001 vs. teetotalers). Maximal % FMD rose (to 10.6 ± 6.2, p < 0.04), but it still remained impaired (<0.04 vs. teetotalers). ADMA increased further to 0.64 ± 0.15 µmol/l (<0.05 vs. baseline, <0.02 vs. teetotalers). CONCLUSIONS: HA show marked endothelial dysfunction (ED) and high BP, impaired insulin sensitivity, inflammation, increased oxidative stress, and elevated ET-1 and ADMA, which are unaffected or only partially reversed by a medium-term alcohol withdrawal. ED and related abnormalities persist in detoxified alcoholics, thus contributing to a greater CV morbidity and mortality.

Serum adipokine zinc α2-glycoprotein and lipolysis in cachectic and noncachectic heart failure patients: relationship with neurohormonal and inflammatory biomarkers.

Chronic heart failure is often complicated by the development of cachexia with the loss of fat mass. Zinc α2-glycoprotein (ZAG) is a serum adipokine with lipolytic effects in cancer cachexia. We evaluated in patients with advanced heart failure with (CxHF) or without cachexia (nCxHF) the relationship of ZAG with circulating free fatty acid (FFA), as an index of lipolysis, and with other neurohormonal and inflammatory biomarkers. Two groups, nCxHF (n = 46) and CxHF (n = 18), the latter having a documented, involuntary, edema-free loss of body weight of at least 7.5% in the previous 6 months, underwent plasma determination of FFA, ZAG, norepinephrine (NE), tumor necrosis factor-α, and natriuretic peptide levels (atrial natriuretic, B-type natriuretic peptide). The patients were compared with age-matched healthy controls (CTR) (n = 21). Zinc α2-glycoprotein, atrial natriuretic peptide, B-type natriuretic peptide, and tumor necrosis factor-α circulating levels were similarly greater in CxHF and nCxHF than in CTR. Free fatty acid and NE were higher in CxHF than in nCxHF. A positive correlation between FFA and NE was found in both CxHF (r = 0.73, P < .01) and nCxHF (r = 0.48, P < .01) but only in CxHF between ZAG and FFA (r = 0.54, P = .02) and between ZAG and NE (r = 0.70, P < .01). No correlations between natriuretic peptides and ZAG were found. Serum ZAG levels are increased in advanced heart failure patients compared with CTR, without differences between CxHF and nCxHF. Only in CxHF, ZAG levels are directly correlated to circulating levels of FFA and NE, suggesting a close interaction of ZAG with sympathetic-mediated lipolysis.

Usefulness of myocardial performance index in multiple sclerosis mitoxantrone-induced cardiotoxicity.

AIMS: The authors sought to investigate the ability of the Doppler-derived myocardial performance index (MPI) to predict cardiotoxicity in multiple sclerosis (MS) patients under mitoxantrone therapy. METHODS AND RESULTS: The aauthors prospectively evaluated 28 MS patients (mean age 41±9 years, 12 males and 16 females) treated with low-dose mitoxantrone (basal mean cumulative dose 30±14 mg/m(2), end of follow-up mean dose 41±17 mg/m(2)). All patients underwent two-dimensional and Doppler-echocardiography at baseline and after a mean follow-up of 22±8 months. MPI was estimated using mitral inflow and left ventricular (LV) outflow pattern. Comparing data at baseline and at the end of follow-up, significant decrease in ejection fraction (EF) was observed (60±5 vs 56±4, p<0.03). The MPI was 0.52±0.1 at baseline and 0.60±0.1 at the end of follow-up (p<0.04). Such difference was mainly due to a isovolumic relaxation time prolongation (80±12 at baseline and 98±30 at the end of follow-up, p<0.05). The area under the receiver operating characteristic curve, analysed for an MPI cut-point value of 0.57, in identifying a significant reduction of LVEF ≤50% was of 0.94±0.065 with sensitivity and specificity of 97.5% and 90%, respectively. CONCLUSION: In conclusion, it can be speculated that a higher basal value of MPI could represent a subclinical LV cardiotoxicity, identifying a future decrease of EF and a progression to congestive heart failure in MS patients under mitoxantrone therapy.

Normotensive male offspring of essential hypertensive parents show early changes in left ventricular geometry independent of blood pressure.

For the purpose of detecting early left ventricle (LV) abnormalities in normotensive offspring of hypertensive parents (EH+), 23 normotensive sedentary male EH+ (age 25 ± 3 years) and 20 matched offspring of normotensive families (EH-), underwent: clinic bloop pressure (BP) measurement, 24-hour ambulatory BP monitoring (ABPM), frequency-domain parameters of autonomic heart rate control and conventional and Doppler tissue echocardiographic (DTE) study of both ventricles, including relative wall thickness (RWT) as an index of LV remodeling. EH+ subjects had slightly higher office systolic and diastolic (P < 0.05), average 24-hour systolic (P < 0.001), diastolic (P < 0.01), and mean BP (P < 0.05). No between-group differences were detected for heart rate variability, LV mass and systolic and diastolic function in both ventricles. RWT was greater in EH+ (0.38 ± 0.05 vs. 0.34 ± 0.03 SD; P < 0.01), which was significantly related, at the univariate analysis, to the condition of EH+ (P < 0.004) and to the clinic and ambulatory BP parameters as well (P = 0.06-0.01). However, at the stepwise multiple regression analysis, with RWT used as the dependent variable, only the condition of EH+ was independently associated with RWT (P < 0.008), whereas BP did not. RWT, according to receiver operating characteristic curves analysis, predicted the condition of EH+ (cutoff point 0.369, specificity 90%, sensitivity 65%). Our data suggest that an higher RWT, as an index towards LV concentric remodeling, is the earliest change in LV geometry in EH+ subjects, independent of any slight elevation in BP. Thus, RWT measurement may be a quite specific tool to detect early LV alterations due to the condition of EH+.

Benefit of prostaglandin infusion in severe heart failure: preliminary clinical experience of repetitive administration.

BACKGROUND: Prostaglandin E1 (PGE1) is a potent vasodilating drug, which has been used in treatment of primary pulmonary hypertension. However intravenous PGE1 infusion may be of benefit and also has been proposed as a therapeutic tool in patients with end-stage heart failure. The aim of this prospective not randomized study was to assess the clinical and instrumental effects of this agent in patients with severe heart failure and pulmonary hypertension. METHODS: To investigate the effects of PGE1 in congestive heart failure we selected 22 consecutive patients (16 males, 6 females, mean age 63±2 years) in the mean NYHA class III, because they had pulmonary hypertension (PAPs>3 m/s and left ventricular ejection fraction (LVEF) ≤35% by echocardiography. A control group of 23 patients (19M, 4F mean age 62±5 years; 9 patients were in the NYHA class IV and 14 in the NYHA class III), with the same instrumental and clinical data, received an optimized oral treatment with beta-blockers, ACE-inhibitors, furosemide and digitalis. Right heart catheterization was performed to confirm and determine the type of pulmonary hypertension, before starting the PGE1 infusion. Clinical and echocardiography evaluation was performed during follow-up. PGE1 was infused at a mean dose of 10 ng/kg/min for a total of 24 h over three consecutive days every three months. RESULTS: Right heart catheterization confirmed a high systolic pulmonary pressure in all patients; pre-capillary pulmonary hypertension (mean PAP>25 mm/Hg) was 25%. During a mean follow-up of 36±6 months, 16 patients died (10 in the control group and 6 in the PGE1 group). The Kaplan-Meier 3-years survival analysis was not statistically significant (Log-rank test), but at 2 months survival rates began to diverge; 36 months survival: 72.7% in the PGE1 group and 56% in the control group. The mean LVEF increased from 25.78% to 32.1% in the PGE1 group and from 23.38% to 26.15 in the control group (p<0.001); the NYHA mean class improved from 3.18 to 2.24 in the PGE1 group and from 3.46 to 3.38 in the control group (p<0.05). The PAP decreased from 57.65 to 40.82 mm/Hg (p<0.001). An AICD was implanted in 3 patients in the first group and in 5 patients in the control group. Two patients were added to the heart transplantation list. CONCLUSION: These preliminary data suggest that intermittent PGE1 infusion in patients with advanced congestive heart failure and high pulmonary pressure is able to improve NYHA mean class (p<0.05), ventricular contractility (LVEF p<0.001), pulmonary pressure and clinical data. It hasn't been associated to morbid events or increased risk of death.

Contribution of bradykinin B2 receptors to the inhibition by valsartan of systemic and renal effects of exogenous angiotensin II in salt-repleted humans.

To investigate whether bradykinin (BK) participates in the inhibition of renal effects of exogenous angiotensin II (AngII) by AngII type 1 receptor (AT1R) blockade, eight salt-repleted volunteers underwent four p-aminohippurate- and inulin-based renal studies of AngII infusion at increasing rates of 0.625, 1.25, and 2.5 ng.kg.min(-1) for 30 min. Studies 1 and 2 were preceded by 3 days of placebo, whereas studies 3 and 4 used 240 to 320 mg.day(-1) valsartan. Bradykinin B2-type receptor (BKB2R) antagonist icatibant (50 mug.kg(-1)) was coinfused in studies 2 and 4. Mean blood pressure (MBP), glomerular filtration rate (GFR), renal blood flow (RBF), and renal sodium excretion (UNaV) were measured. In study 1, MBP rose by 12.8%, UNaV decreased by 68%, and GFR and RBF also fell (p < 0.001 for all). In study 2, GFR and RBF fell as in study 1, but the rise in MBP and the fall in UNaV were accentuated [+20.0%, analysis of variance (ANOVA), p < 0.02 versus study 1 and -80.0%, p < 0.05, respectively]. In study 3, AngII had no effects, and in study 4, renal hemodynamics remained unaffected, but MBP still rose and UNaV fell (ANOVA, p < 0.02 and 0.005 versus study 3, respectively). Icatibant accentuated AngII-induced changes in MBP and UNaV. Previous AT1R blockade prevented any systemic and renal effects of AngII, but significant changes in MBP and UNaV still followed AngII plus icatibant even after AT1R blockade. BK, through BKB2Rs, participates in the inhibitory action of AT1R blockers toward actions of exogenous AngII on MBP and UNaV in healthy humans.

Long-term effects of perindopril on left ventricular structure and function in patients with stable coronary artery disease: a conventional and Doppler tissue echocardiographic pilot study.

OBJECTIVES: The aim of this study was to investigate the long-term effects of perindopril on left ventricular (LV) systolic and diastolic function in patients with stable coronary artery disease who had previously undergone coronary artery bypass graft. METHODS: Thirteen patients (12 male and one female patient) were treated with perindopril 8 mg/day and 13 (nine male and four female patients) with placebo, and both groups underwent conventional and Doppler tissue echocardiography (DTE) at baseline and after 12, 24, 36 and 47 months. DTE was sampled at the four sites of the mitral annulus and peak velocity (pv) and the time-velocity integral (tvi) of systolic (S) and diastolic (E and A) waves were calculated. RESULTS: During the 47 months of follow-up, ejection fraction significantly increased in the perindopril group from 58 +/- 10 to 69 +/- 6% (P < 0.01) without any significant change in LV volumes. LV shortening and relaxation, assessed by DTE, also significantly increased: Stvi from 1.57 +/- 0.18 to 1.95 +/- 0.19 cm (P < 0.01) and Etvi from 0.95 +/- 0.23 to 1.37 +/- 0.59 cm (P < 0.05). There were no changes in ejection fraction (64 +/- 6 vs. 65 +/- 8%; P = not significant) or S or E waves in the placebo group, but a significant increase in LV diastolic volume. Blood pressure remained unchanged in both groups. CONCLUSION: Our data suggest that perindopril improves both systolic and diastolic LV myocardial performance, a beneficial effect that may be due to the previously demonstrated biological, anti-ischemic and endothelium-dependent action of perindopril.

[Echocardiography in internal medicine: usefulness of Doppler tissue analysis]. / Ecocardiografia in ambito internistico: contributo dell'analisi Doppler tissutale.

The Doppler echocardiographic examination is the most important and common method used for cardiac imaging due to its safety, its relatively low cost and the great amount of morphofunctional information it can provide. It also plays a relevant role in the assessment of cardiac involvement underlying systemic diseases, in most of which the complication rate is often subclinical and represents one of the main causes of mortality. Advances in technology have lead to an increase in diagnostic accuracy and the range of applications of echocardiography. Among the new techniques, tissue Doppler echocardiography has been shown to identify early ventricular changes in both diastolic and systolic phases and in the preclinical stage of systemic diseases such as amyloidosis, systemic lupus erythematosus, vasculitis, with possible cardiac involvement. The increased sensitivity derives from the possibility of assessing longitudinal mechanics, which seems affected earlier than the circumferential one by pathological processes. Tissue Doppler echocardiography analysis, associated with a complete clinical history, can make an early diagnosis or arise a diagnostic suspicion to the physician, allowing early detection and rapid implementation of diagnostic and therapeutic measures able to improve patient prognosis.

Impaired renal haemodynamic response to L-arginine in essential hypertension: role of buffering anion and tubuloglomerular feedback.

OBJECTIVE: To investigate whether changes in tubuloglomerular feedback (TGF) dependent upon the tubular effects of buffering anions affect the renal haemodynamic response to L-arginine in healthy (control) individuals and patients with essential hypertension. METHODS: Mean arterial pressure (MAP), glomerular filtration rate (GFR), renal blood flow (RBF) and fractional excretion of sodium (FENa), chloride (FECl) and lithium (FELi) were measured in 10 control individuals and 10 hypertensive patients during two 3-h infusions of 0.012 mmol/kg per min L-arginine buffered with either HCl or citric acid. RESULTS: FELi, FECl and FENa increased (P < 0.001) comparably in controls and hypertensive individuals with arginine-HCl and decreased with arginine-citrate (P < 0.001). MAP was unchanged in controls with arginine-HCl and decreased by 3% with arginine-citrate (P < 0.001), and decreased in hypertensive individuals with both arginine-HCl and arginine-citrate (by 3 and 7%, respectively; P < 0.001). GFR increased with arginine-citrate in controls and hypertensive individuals (by 6.1 and 5.4%, respectively; P < 0.001), but did not change with arginine-HCl in controls and declined by 4.6% in hypertensive individuals (P < 0.05). RBF increased equally after arginine-citrate in controls and hypertensive individuals (by 34 and 33%, respectively; P < 0.001); it also increased after arginine-HCl (22 and 13%, respectively; P < 0.001), but less than after arginine-citrate (P < 0.001), and 41% less in hypertensive individuals than in controls (P < 0.001). DISCUSSION: Because arginine-HCl, unlike arginine-citrate, inhibits tubular reabsorption and elicits much less renal vasodilatation than does arginine-citrate, renal haemodynamics in response to L-arginine are modulated by changes in reabsorption and TGF according to the tubular effects of the attendant anion. As renal vasodilatation in hypertensive individuals was reduced only with arginine-HCl, which activates TGF, the blunted vasodilatation of the hypertensive kidney in response to arginine-HCl reflects an exaggerated response to an activated TGF.