Loss of Mrap2 is associated with Sim1 deficiency and increased circulating cholesterol.

Melanocortin receptor accessory protein 2 (MRAP2) is a transmembrane accessory protein predominantly expressed in the brain. Both global and brain-specific deletion of Mrap2 in mice results in severe obesity. Loss-of-function MRAP2 mutations have also been associated with obesity in humans. Although MRAP2 has been shown to interact with MC4R, a G protein-coupled receptor with an established role in energy homeostasis, appetite regulation and lipid metabolism, the mechanisms through which loss of MRAP2 causes obesity remains uncertain. In this study, we used two independently derived lines of Mrap2 deficient mice (Mrap2(tm1a/tm1a)) to further study the role of Mrap2 in the regulation of energy balance and peripheral lipid metabolism. Mrap2(tm1a/tm1a) mice have a significant increase in body weight, with increased fat and lean mass, but without detectable changes in food intake or energy expenditure. Transcriptomic analysis showed significantly decreased expression of Sim1, Trh, Oxt and Crh within the hypothalamic paraventricular nucleus of Mrap2(tm1a/tm1a) mice. Circulating levels of both high-density lipoprotein and low-density lipoprotein were significantly increased in Mrap2 deficient mice. Taken together, these data corroborate the role of MRAP2 in metabolic regulation and indicate that, at least in part, this may be due to defective central melanocortin signalling.

Pulmonary embolism severity index accurately predicts long-term mortality rate in patients hospitalized for acute pulmonary embolism.

BACKGROUND: The Pulmonary Embolism (PE) Severity Index (PESI) is a clinical prognostic rule that accurately classifies PE patients into five risk classes with increasing mortality. PESI score has been validated in studies with a relatively short-term follow-up and its accuracy in predicting long-term prognosis has never been established. METHODS: Consecutive patients admitted to the tertiary care hospital of Varese (Italy) with an objectively diagnosed PE between January 2005 and December 2009 were retrospectively included. Information on clinical presentation, diagnostic work-up, risk factors, treatment and mortality during a 1-year follow-up was collected. RESULTS: Five hundred and thirty-eight patients were enrolled in this study. The mean age was 70.6 years (± SD 15.2), 44.4% of patients were male, and 27.9% had known cancer. One-year follow-up was available for 96.1% of patients. The overall mortality rate was 23.2% at 3 months, 30.2% at 6 months and 37.1% at 12 months. The discriminatory power of the PESI score to predict long-term mortality, expressed as the area under the ROC curve, was 0.77 (95%CI, 0.72-0.81) at 3 months, 0.77 (95%CI, 0.73-0.81) at 6 months and 0.79 (95%CI, 0.75-0.82) at 12 months. The PESI score confirmed its accurate prediction in patients without cancer. Simplified PESI had a similar overall accuracy to the original PESI at 3 and 6 months, but this was significantly lower at 1 year. CONCLUSIONS: The results of this study suggest that PESI score may also be an accurate tool to define the 6-month and 1-year mortality rates in PE patients.

Diagnostic accuracy of lung ultrasound for pulmonary embolism: a systematic review and meta-analysis.

BACKGROUND: Computed tomographic pulmonary angiography (CTPA) has simplified the diagnostic approach to patients with suspected pulmonary embolism (PE). However, PE diagnosis is still probabilistic and CTPA should be used with caution in some patient groups, such as patients with severe renal insufficiency and pregnant women. Among alternative imaging tests, lung ultrasound is the most promising technique. We aimed to systematically assess the diagnostic accuracy of lung ultrasound for PE diagnosis. METHODS: Studies evaluating the diagnostic accuracy of lung ultrasound for the diagnosis of PE were systematically searched for in the MEDLINE and EMBASE databases (up to June 2012). The QUADAS-2 tool was used for the quality assessment of the primary studies. A bivariate random-effects regression approach was used for summary estimates of both sensitivity and specificity. RESULTS: Ten studies, for a total of 887 patients, were included. A composite reference test was used in six studies, with single-row detector CTPA as the principal imaging test in four studies. Overall, seven studies used a proper reference test. Lung ultrasound bivariate weighted mean sensitivity was 87.0% (95% confidence interval [CI] 79.5, 92.0%), whereas bivariate weighted mean specificity was 81.8% (95% CI 71.0, 89.3%). CONCLUSIONS: Our findings suggest that lung ultrasound may be a useful diagnostic tool in the management of patients with suspected PE. However, several methodological drawbacks of the primary studies limit any definite conclusion. Further well-designed accuracy studies are necessary before planning diagnostic management studies, in particular in those with a contraindication for CTPA.

Left ventricular remodeling in patients with metabolic syndrome: influence of gender.

AIM: The study was aimed to evaluate the influence of gender on left ventricular (LV) remodeling in metabolic syndrome (MetS). METHODS AND RESULTS: We enrolled 200 subjects without diabetes or overt cardiovascular diseases, never treated with anti-hypertensive drugs or statins: 60 men and 40 women with MetS matched by age, gender and 24 h systolic and diastolic blood pressure (BP) with 60 men and 40 women without MetS. The patients underwent blood tests, 24 h our BP monitoring, LV echocardiographic examination. LV mass indexed by eight(2.7) was significantly greater in men and women with MetS than without MetS. Compared with women without MetS, women with MetS had significantly higher posterior wall thickness and relative wall thickness, greater prevalence of LV concentric remodeling/hypertrophy and lower indices of LV diastolic function, whereas all these parameters were not significantly different between men with and without MetS. MetS was an independent predictor of relative wall thickness and LV mass index in women, but not in men. CONCLUSION: The impact of MetS on LV remodeling is significantly influenced by gender: the effects of MetS are more pronounced in women, with development of LV concentric hypertrophy/remodeling and preclinical diastolic dysfunction.

Left ventricular remodelling in asymptomatic HIV infection on chronic HAART: comparison between hypertensive and normotensive subjects with and without HIV infection.

The high cardiovascular risk of HIV infected (HIV+) patients is still partly unexplained. We aimed to evaluate if HIV infection and highly active antiretroviral therapy (HAART) are linked per se to left ventricular (LV) remodelling, independently of blood pressure (BP) values. We enrolled 4 groups of patients matched by gender, age, body mass index and smoking habit: 30 HIV+ hypertensives, 30 HIV+ normotensives, 30 not-infected (HIV-) hypertensives and 30 HIV- normotensives. HIV+ patients were on chronic HAART. Hypertension was newly diagnosed (≤6 months) and never treated. Each patient underwent blood tests, 24-h BP monitoring and LV echocardiogram. The 4 groups had similar fasting glucose and cholesterol; triglycerides, HOMA index and prevalence of metabolic syndrome were higher in the HIV+ groups. Despite similar 24-h BP values, HIV+ hypertensives had greater LV mass and higher prevalence of preclinical diastolic dysfunction than HIV- hypertensives. Compared to HIV- normotensives, HIV+ normotensives had similar 24-h BP values, but greater LV mass and lower LV diastolic indices, similar to HIV- hypertensives, whose 24-h BP values were higher. Asymptomatic HIV infection and chronic HAART are associated with myocardial hypertrophy and preclinical diastolic dysfunction, independently of BP values.

Components of arterial systolic pressure and RR-interval oscillation spectra in a case of baroreflex failure, a human open-loop model of vascular control.

The baroreflex control of circulation is always operating and modulates blood pressure and heart rate oscillations. Thus, the study of cardiovascular variability in humans is performed in a closed-loop model and the physiology of post-sinoaortic denervation is completely unknown in humans. We dissected for the first time the different components of systolic arterial pressure (SAP) and RR-interval spectra in a patient with 'baroreflex failure' (due to mixed cranial nerve neuroma) who represents a human model to investigate the cardiovascular regulation in an open-loop condition. Interactions among cardiovascular variability signals and respiratory influences were described using the multivariate parametric ARXAR model with the following findings: (1) rhythms unrelated to respiration were detected only at frequencies lower than classical low frequency (LF; Slow-LF, around 0.02 Hz) both in SAP an RR spectra, (2) small high-frequency (HF) modulation is present and related with respiration at rest and in tilt (but for SAP only) and (3) the Slow-LF fluctuations detected both in SAP and RR oscillate independently as the multivariate model shows no relationships between SAP and RR, and these oscillations are not phase related. Thus, we showed that in a patient with impaired baroreflex arc integrity the Slow-LF rhythms for RR have a central origin that dictates fluctuations on RR at the same rhythm but unrelated to the oscillation of SAP (which may be related with both peripheral activity and central rhythms). The synchronization in LF band is a hallmark of integrity of baroreflex arc whose impairment unmasks lower frequency rhythms in SAP and RR whose fluctuations oscillate independently.

Changes in autonomic modulation to the heart and intracellular catecholamines. A longitudinal study in differentiated thyroid carcinoma during short-term hypothyroidism and thyroid hormone replacement.

BACKGROUND: The effects of thyroid deprivation on the autonomic modulation to the heart remain controversial. METHODS: In this study in patients followed for thyroid carcinoma, we investigated (1) heart rate variability parameters and the baroreflex gain and (2) intracellular catecholamine levels in circulating lymphocytes during short-term hypothyroidism (phase 1) and after reinstitution of TSH-suppressive thyroid hormone replacement (phase 2). RESULTS: The RR interval value (p < 0.01) and systolic blood pressure (p < 0.05) were higher in phase 1 than in phase 2. The low-frequency/high-frequency (LF/HF) ratio was significantly lower in the hypothyroid state (p < 0.05), with a higher HF component (p < 0.05). After adjusting for mean RR interval in the regression model, the difference between the power of RR interval oscillations calculated in the two states was greater for the LF band (p = 0.005) and it was borderline significant for the HF band (p = 0.052). The baroreflex gain alpha(LF) index was similar in the two phases. The stimulus-induced cellular production of norepinephrine and epinephrine in peripheral blood mononuclear cells was significantly higher in phase 2. CONCLUSION: The neurally-mediated influences on the sinus node and the study of intracellular catecholamine production suggest a reduced sympathoexcitation in hypothyroidism compared with the treatment phase. The early increase in blood pressure observed after thyroid hormone withdrawal is not due to impaired sensitivity of the baroreflex arc.

Thyroid hormone and thyrotropin regulate intracellular free calcium concentrations in human polymorphonuclear leukocytes: in vivo and in vitro studies.

Intracellular free calcium concentrations (Ca++i) were studied in polymorphonuclear leukocytes (PMNs) from 13 athyreotic patients who had been previously treated by total thyroidectomy and radioiodine therapy for differentiated thyroid carcinoma, and from age- and sex-matched euthyroid healthy controls. Patients were studied twice, when hypothyroid (visit 1) and after restoration of euthyroidism by L-T4 TSH-suppressive therapy (visit 2). PMNs from patients at visit 1 had significantly lower resting (Ca++)i levels compared to both visit 2 and controls. Values at visit 2 did not differ from those of the controls. Stimulus-induced (Ca++)i rise was also significantly blunted at visit 1 and normalized at visit 2, possibly through a differential contribution of distinct intracellular Ca++ stores, as suggested by the response pattern to the chemotactic agent, N-formyl-Met-Leu-Phe (fMLP), to the selective SERCA pump inhibitor, thapsigargine, and to the mitochondrial uncoupler, carbonyl cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP). In vitro treatment of PMNs from healthy subjects with high TSH concentrations impaired intracellular Ca++ store function. Both resting (Ca++)i levels and fMLP-induced (Ca++)i rise increased in the presence either of low-concentration TSH or of T4, but effects of TSH and T4 were not additive. T3, rT3, and TRIAC had no effect. In conclusion, this study provides evidence for a direct relationship between thyroid status and (Ca++)i homeostasis in human PMNs, mainly related to direct actions of TSH and T4 on these cells.

Interneurons transiently express the ERG K+ channels during development of mouse spinal networks in vitro.

During spinal cord maturation neuronal excitability gradually differentiates to meet different functional demands. Spontaneous activity, appearing early during spinal development, is regulated by the expression pattern of ion channels in individual neurons. While emerging excitability of embryonic motoneurons has been widely investigated, little is known about that of spinal interneurons. Voltage-dependent K+ channels are a heterogeneous class of ion channels that accomplish several functions. Recently voltage-dependent K+ channels encoded by erg subfamily genes (ERG channels) were shown to modulate excitability in immature neurons of mouse and quail. We investigated the expression of ERG channels in immature spinal interneurons, using organotypic embryonic cultures of mouse spinal cord after 1 and 2 weeks of development in vitro. We report here that all the genes of the erg family known so far (erg1a, erg1b, erg2, erg3) are expressed in embryonic spinal cultures. We demonstrate for the first time that three ERG proteins (ERG1A, ERG2 and ERG3) are co-expressed in the same neuronal population, and display a spatio-temporal distribution in the spinal slices. ERG immuno-positive cells, representing mainly GABAergic interneurons, were present in large numbers at early stages of development, while declining later, with a ventral to dorsal gradient. Patch clamp recordings confirmed these data, showing that ventral interneurons expressed functional ERG currents only transiently. Similar expression of the erg genes was observed at comparable ages in vivo. The role of ERG currents in regulating neuronal excitability during the earliest phases of spinal circuitry development will be examined in future studies.

Physical and functional interaction between integrins and hERG potassium channels.

Integrins are adhesion receptors capable of transmitting intracellular signals that regulate many different cellular functions. Among integrin-mediated signals, the activation of ion channels can be included. We demonstrated that a long-lasting activation of hERG (human ether-a-go-go-related gene) potassium channels occurs in both human neuroblastoma and leukaemia cells after the activation of the beta1 integrin subunit. This activation is apparently a determining factor inducing neurite extension and osteoclastic differentiation in both the cell types. More recently, we provided evidences that beta1 integrins and hERG channels co-precipitate in both the cell types. Preliminary results suggest that a macromolecular signalling complex indeed occurs between integrins and the hERG1 protein and that hERG channel activity can modulate integrin downstream signalling.

Natriuretic peptides as markers of preclinical cardiac disease in obesity.

BACKGROUND: Aim of the study was to evaluate the role of atrial (ANP) and brain natriuretic peptides (BNP) as markers of preclinical cardiac disease in obesity. METHODS: We selected 26 obese (BMI > 29 kg m(-2)) never-treated hypertensives (24-h BP > 140 and/or 90 mmHg), 26 obese normotensives (24-h BP < 130/80 mmHg) and 25 lean (BMI < or = 25 kg m(-2)) never-treated hypertensives. Each subject underwent measurements of ANP and BNP plasma levels, 24-h ambulatory blood pressure (BP) monitoring, digitized M-mode and Doppler echocardiography. RESULTS: Mean values of ANP and BNP were similar among the three groups. All the subjects had normal left ventricular (LV) systolic function. Within each group ANP levels were higher in patients with LV diastolic dysfunction than in patients with normal diastolic function, and BNP levels were higher in patients with LV hypertrophy and in patients with LV diastolic dysfunction. Within each group, ANP levels were inversely correlated with LV diastolic indices, whereas BNP levels were directly correlated with LV mass index and inversely correlated with LV diastolic indices. ANP and BNP levels were not correlated with other echocardiographic parameters, age, BMI or 24-h BP values. CONCLUSION: In normotensive and hypertensive obese subjects the relationships of ANP and BNP levels with LV morpho-functional characteristics follow the same trend as in lean hypertensives, with ANP mainly influenced by diastolic dysfunction and BNP influenced by both LV hypertrophy and LV diastolic dysfunction. Therefore ANP and BNP can be considered useful markers of preclinical cardiac disease in obesity.

HERG potassium channels are constitutively expressed in primary human acute myeloid leukemias and regulate cell proliferation of normal and leukemic hemopoietic progenitors.

An important target in the understanding of the pathogenesis of acute myeloid leukemias (AML) relies on deciphering the molecular features of normal and leukemic hemopoietic progenitors. In particular, the analysis of the mechanisms involved in the regulation of cell proliferation is decisive for the establishment of new targeted therapies. To gain further insight into this topic we report herein a novel approach by analyzing the role of HERG K(+) channels in the regulation of hemopoietic cell proliferation. These channels, encoded by the human ether-a-gò-gò-related gene (herg), belong to a family of K(+) channels, whose role in oncogenesis has been recently demonstrated. We report here that herg is switched off in normal peripheral blood mononuclear cells (PBMNC) as well as in circulating CD34(+) cells, however, it is rapidly turned on in the latter upon induction of the mitotic cycle. Moreover, hergappears to be constitutively activated in leukemic cell lines as well as in the majority of circulating blasts from primary AML. Evidence is also provided that HERG channel activity regulates cell proliferation in stimulated CD34(+) as well as in blast cells from AML patients. These results open new perspectives on the pathogenetic role of HERG K(+) channels in leukemias.

Left ventricular changes in isolated office hypertension: a blood pressure-matched comparison with normotension and sustained hypertension.

BACKGROUND: Isolated office (IO) hypertension is a benign condition according to some researchers, whereas others believe it is associated with cardiovascular abnormalities and increased cardiovascular risk. The aim of this study is to compare morphofunctional characteristics of the left ventricle (LV) in IO hypertensive subjects, normotensive subjects (hereafter, hypertensives and normotensives), and never-treated sustained hypertensives. The 3 groups were matched not only by age, sex, and body mass index but also by clinic blood pressure (BP) (IO hypertensives and sustained hypertensives) and daytime BP (IO hypertensives and normotensives). METHODS: We enrolled 42 IO hypertensives (clinic BP > 140 and/or 90 mm Hg and daytime BP < or = 130/80 mm Hg), 42 sustained hypertensives (clinic BP > 140 and/or 90 mm Hg and daytime BP > or = 140 and/or 90 mm Hg) and 42 normotensives (clinic BP < 135 and/or 85 mm Hg and daytime BP < or = 130/80 mm Hg). Left ventricular morphologic features and function were assessed using digitized M-mode echocardiography. RESULTS: Compared with normotensives, IO hypertensives had significantly thicker LV walls, increased LV mass, reduced diastolic function, increased prevalence of LV hypertrophy, and preclinical diastolic dysfunction. Sustained hypertensives, compared with IO hypertensives, had significantly thicker LV wall, higher LV mass, and lower diastolic function, whereas the prevalence of LV hypertrophy and preclinical diastolic dysfunction was greater than in IO hypertensives, but the difference did not reach statistical significance (P = .29). CONCLUSIONS: Comparing matched BP groups, IO hypertensives have LV morphofunctional characteristics considerably different from normotensives and qualitatively similar to sustained hypertensives. Therefore, our results support the hypothesis that IO hypertension should not be considered as simply a benign condition.

Autonomic function and baroreflex sensitivity during angiotensin-converting enzyme inhibition or angiotensin II AT-1 receptor blockade in essential hypertensive patients.

OBJECTIVE: The influence of ACE-inhibition and angiotensin II ATI receptor blockade on the autonomic function and baroreflex sensitivity was investigated in hypertension. METHODS AND RESULTS: Heart rate variability was assessed in a resting condition by power spectrum analysis to evaluate the low frequency (LF) power, high frequency (HF) power and LF/HF ratio in 19 hypertensive patients and 23 normotensive controls. Moreover, the coherence between the tachogram and the systogram was evaluated, and the baroreflex gain (alphaLF-index), describing the transfer function of variability in the systolic pressure signal to variability in the RR interval, was obtained. Then a 24-h ambulatory blood pressure monitoring was performed. The 19 hypertensive patients were randomized to either enalapril or losartan treatment, and after 2 months were re-submitted to the RR variability and baroreflex study and to blood pressure monitoring. The subjects then crossed to the other antihypertensive treatment and were re-evaluated after an additional two months. No significant difference was found either in LF power and HF power and LF/HF ratio between normotensive and hypertensive subjects whereas a slight though significant difference was observed in the alphaLF-index. In hypertensive patients, both the treatments with enalapril and losartan reduced blood pressure and had no effect on heart rate. No significant change was observed in autonomic balance or in baroreflex sensitivity during the two antihypertensive treatments. CONCLUSIONS: In hypertensive patients, the angiotensin system or bradykinins do not seem to have any modulatory effect on the sympathetic/parasympathetic control of blood pressure and baroreflex sensitivity, in a resting condition. Since heart rates were unchanged by the two antihypertensive treatments despite a significant reduction of blood pressure, a resetting of baroreflex function was observed during both ACE-inhibition and angiotensin II ATI receptor blockade.

Microalbuminuria as a marker of preclinical diastolic dysfunction in never-treated essential hypertensives.

Using 24-h ambulatory blood pressure (BP) monitoring and digitized M-mode echocardiography, we evaluated whether microalbuminuria is related to preclinical left ventricular (LV) diastolic dysfunction in hypertensive patients. We selected 87 never-treated hypertensive patients (mean 24-h BP > 140 and/or > 90 mm Hg); albuminuria was evaluated as mean value of 24-h urinary albumin excretion (UAE) from two 24-h urine collections. Microalbuminuria was found in 28 patients, classified as MA+ (UAE 30 to 300 mg/24 h); 59 patients had normal UAE (< 30 mg/24 h) and were classified as MA-. The MA+ and MA- groups did not differ with regard to age, sex, body mass index, or 24-h heart rate, whereas 24-h, daytime, and nighttime systolic and diastolic BP were significantly higher in MA+ than in MA-. The LV mass index was greater in MA+, as was the prevalence of LV hypertrophy; peak shortening rate of LV diameter, index of systolic function, was normal in all, but was lower in MA+. Peak lengthening rate of LV diameter and peak thinning rate of posterior wall, indices of diastolic function, were lower in MA+ and the prevalence of diastolic dysfunction was higher in MA+. UAE was inversely correlated with both indices of LV diastolic function, also after correction for age, 24-h heart rate, 24-h BP, and LV mass. In conclusion, in never-treated hypertensive patients, microalbuminuria is not only associated with greater myocardial mass, but is also related with preclinical impairment of LV diastolic function. This relation, independent from increased BP or LV mass, strengthens the role of microalbuminuria as an early and reliable marker of preclinical cardiac involvement.

Longitudinal changes of insulin sensitivity in essential hypertension: influence of blood pressure control and familial predisposition to hypertension.

The aim of this study was to evaluate the influence of blood pressure (BP) control and familial predisposition to hypertension on longitudinal changes in insulin sensitivity in essential hypertension. We evaluated 6 groups of subjects twice (basal: before any treatment; 2nd: after at least 18 months): 42 hypertensives (H) with a family history of hypertension (F+) and 30 H without a family history of hypertension (F-) successfully treated with angiotensin-converting enzyme inhibitors and/or calcium channel blockers (2nd: 24-h BP < or = 130/80 mm Hg); 22 untreated (UT) HF+ and 18 UTHF- (2nd: 24-h BP >140 and/or 90 mm Hg); 18 normotensives F+ and 15 normotensives F-. The parameters evaluated were as follows: glucose, insulin, and C-peptide (Cp) response to an oral glucose load. Glucose was normal in all of the subjects, similar among the 6 groups, and unchanged at the 2nd evaluation. At the basal evaluation insulin and Cp were higher and the metabolic clearance rate (MCR) of glucose was lower in the three F+ groups compared with the corresponding F- groups. In the 2nd evaluation insulin and Cp were reduced and the MCR of glucose increased in THF-, whereas all metabolic parameters were unchanged in THF+; in both UT hypertensive groups insulin and Cp increased and the MCR of glucose decreased, more so in F+ than in F-; in normotensive groups metabolic parameters did not change. A familial predisposition to hypertension influences insulin sensitivity changes during successful antihypertensive therapy, with an improvement in insulin sensitivity in F- and no changes in F+. A persistently high BP has a negative influence on insulin sensitivity in F+ and F-; this influence is greater when high BP is associated with a familial predisposition to hypertension.

HERG K+ channels activation during beta(1) integrin-mediated adhesion to fibronectin induces an up-regulation of alpha(v)beta(3) integrin in the preosteoclastic leukemia cell line FLG 29.1.

Integrin receptors have been demonstrated to mediate either "inside-to-out" and "outside-to-in" signals, and by this way are capable of regulating many cellular functions, such as cell growth and differentiation, cell migration, and activation. Among the various integrin-centered signaling pathways discovered so far, we demonstrated that the modulation of the electrical potential of the plasma membrane (V(REST)) is an early integrin-mediated signal, which is related to neurite emission in neuroblastoma cells. This modulation is sustained by the activation of HERG K(+) channels, encoded by the ether-à-go-go-related gene (herg). The involvement of integrin-mediated signaling is being discovered in the hemopoietic system: in particular, osteoclasts are generated as well as induced to differentiate by interaction of osteoclast progenitors with the stromal cells, through the involvement of integrin receptors. We studied the effects of cell interaction with the extracellular matrix protein fibronectin (FN) in a human leukemic preosteoclastic cell line (FLG 29.1 cells), which has been demonstrated to express HERG currents. We report here that FLG 29.1 cells indeed adhere to purified FN through integrin receptors, and that this adhesion induces an osteoclast phenotype in these cells, as evidenced by the appearance of tartrate-resistant acid phosphatase, as well as by the increased expression of CD51/alpha(v)beta(3) integrin and calcitonin receptor. An early activation of HERG current (I(HERG)), without any increase in herg RNA or modifications of HERG protein was also observed in FN-adhering cells. This activation is apparently sustained by the beta(1) integrin subunit activation, through the involvement of a pertussis-toxin sensitive G(i) protein, and appears to be a determinant signal for the up-regulation of alpha(v)beta(3) integrin, as well as for the increased expression of calcitonin receptor.

Obesity and left ventricular diastolic function: noninvasive study in normotensives and newly diagnosed never-treated hypertensives.

OBJECTIVE: To evaluate the influence of obesity, per se or associated with hypertension, on left ventricular (LV) diastolic function. PATIENTS: Thirty-two obese newly-diagnosed never-treated hypertensives; 32 obese normotensives matched for age, sex and BMI with hypertensives; 32 lean newly diagnosed never-treated hypertensives and 32 lean normotensives, matched for age, sex and 24 h blood pressure (BP) with the obese subjects. METHODS: Twenty-four-hour ambulatory blood pressure monitoring and digitized M-mode LV echocardiograms. PARAMETERS EVALUATED: Twenty-four-hour, day-time and night-time BP and heart rate, percentage nocturnal BP fall; LV end-diastolic diameter index, septal and posterior wall thickness, LV mass index, peak shortening and lengthening rate of LV diameter, peak thinning rate of LV posterior wall. RESULTS: A main effect was found for obesity on LV diameter and LV mass and for hypertension on LV mass; LV systolic function was normal in all the subjects and similar among the four groups; LV diastolic function was significantly reduced in both obese groups with respect to lean ones. This difference persisted after correction of diastolic parameters for 24 h BP and heart rate, LV diameter and LV mass index and disappeared only after correction for body mass index. This latter was inversely related with diastolic parameters only in the obese groups. CONCLUSIONS: Obesity is associated with a preclinical impairment of LV diastolic function in both normotensives and hypertensives; the diastolic impairment is independent of haemodynamic factors, such as 24 h BP and heart rate, and bears no relation to LV geometry in normotensives and only little relation in hypertensives, having therefore to be ascribed to obesity itself.