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This study sought to determine the use of intravenous fluids in the early care of patients with acute decompensated heart failure (HF) who are treated with loop diuretics.Intravenous fluids are routinely provided to many hospitalized patients.We conducted a retrospective cohort study of patients admitted with HF to 346 hospitals from 2009 to 2010. We assessed the use of intravenous fluids during the first 2 days of hospitalization. We determined the frequency of adverse in-hospital outcomes. We assessed variation in the use of intravenous fluids across hospitals and patient groups.Among 131,430 hospitalizations for HF, 13,806 (11%) were in patients treated with intravenous fluids during the first 2 days. The median volume of administered fluid was 1,000 ml (interquartile range: 1,000 to 2,000 ml), and the most commonly used fluids were normal saline (80%) and half-normal saline (12%). Demographic characteristics and comorbidities were similar in hospitalizations in which patients did and did not receive fluids. Patients who were treated with intravenous fluids had higher rates of subsequent critical care admission (5.7% vs. 3.8%; p 0.0001), intubation (1.4% vs. 1.0%; p = 0.0012), renal replacement therapy (0.6% vs. 0.3%; p 0.0001), and hospital death (3.3% vs. 1.8%; p 0.0001) compared with those who received only diuretics. The proportion of hospitalizations that used fluid treatment varied widely across hospitals (range: 0% to 71%; median: 12.5%).Many patients who are hospitalized with HF and receive diuretics also receive intravenous fluids during their early inpatient care, and the proportion varies among hospitals. Such practice is associated with worse outcomes and warrants further investigation.

We design and implement an intelligent advisor system for assisting individuals in changing their physical activity behavior. This system monitors an individual's physical activity and provides personalized, dynamic, pace-based recommendations to help an individual attain his/her activity goal. It adapts to a person's real-life constraints and generates recommendations using data from the individual's own activity history as well as data from a cohort of people similar to the individual. Our system relies on frequent predictions of the likelihood of goal attainment throughout the day, so that the current conditions and context are accounted for.

Objectives: This study sought to determine hospital patterns of change in use of nesiritide over a 6-year period after publications of safety concerns in 2005 and to identify hospital characteristi...

Objectives This study sought to determine hospital variation in the use of positive inotropic agents in patients with heart failure. Background Clinical guidelines recommend targeted use of positive inotropic agents in highly selected patients, but data are limited and the recommendations are not specific. Methods We analyzed data from 376 hospitals including 189,948 hospitalizations for heart failure from 2009 through 2010. We used hierarchical logistic regression models to estimate hospital-level risk-standardized rates of inotrope use and risk-standardized in-hospital mortality rates. Results The risk-standardized rates of inotrope use ranged across hospitals from 0.9% to 44.6% (median: 6.3%, interquartile range: 4.3% to 9.2%). We identified various hospital patterns based on the type of agents: dobutamine-predominant (29% of hospitals), dopamine-predominant (25%), milrinone-predominant (1%), mixed dobutamine and dopamine pattern (32%), and mixed pattern including all 3 agents (13%). When studying the factors associated with interhospital variation, the best model performance was with the hierarchical generalized linear models that adjusted for patient case mix and an individual hospital effect (receiver operating characteristic curves from 0.77 to 0.88). The intraclass correlation coefficients of the hierarchical generalized linear models (0.113 for any inotrope) indicated that a noteworthy proportion of the observed variation was related to an individual institutional effect. Hospital rates or patterns of use were not associated with differences in length of stay or risk-standardized mortality rates. Conclusions We found marked differences in the use of inotropic agents for heart failure patients among a diverse group of hospitals. This variability, occurring in the context of little clinical evidence, indicates an urgent need to define the appropriate use of these medications.

Person-generated health data (PGHD) generated by wearable devices and smartphone applications are growing rapidly. There is increasing effort to employ advanced analytical methods to generate insights from these data in order to help people change their lifestyle and improve their health. PGHD—such as step counts, exercise logs, nutritional diaries, and sleep records—are often incomplete, inaccurate, and collected over too short a duration. Insufficient user engagement with wearable and mobile technologies, as well as lack of sensor validation, standardization of data collection, transparency of data processing assumptions, and accessibility to relevant data from consumer-grade sensors, also negatively affects data quality. The literature on data quality for PGHD is sparse and fragmented, providing little guidance to data analysts on how to assess and prioritize data quality concerns. In this paper, we summarize our experiences as data analysts working with PGHD, outline some of the challenges in using PGHD for insight generation, and discuss some established methods for addressing these challenges. We review the literature on PGHD data quality, identify the major stakeholders in the PGHD ecosystem, and apply an established data quality framework to present the most relevant data quality challenges for each stakeholder.

Mammalian target of rapamycin (mTOR) activity is regulated by assembly of two functionally distinct complexes, mTORC1 and mTORC2. In syndecan-4 (S4) null endothelial cells, mTORC2 activity is reduced, resulting in decreased Akt activation, while mTORC1 activity is increased. Levels of rictor, mLST8, and mSin-1 are unchanged in total cell lysates but decreased in the rafts of S4(-/-) endothelial cells, as is the level of PKCalpha. Expression of myristoylated-PKCalpha in S4(-/-) cells restores rictor, mLST8, and mSin-1 presence in the rafts and rescues Akt phosphorylation. PKCalpha knockdown mimics the effect of S4 deletion on mTORC2 localization and Akt activation. Reduced mTORC2 activity in S4(-/-) endothelial cells results in decreased FoxO1/3a and eNOS phosphorylation, decreased endothelial cell size, and increased arterial blood pressure in S4(-/-) mice. Thus, S4-dependent targeting of PKCalpha to the plasma membrane is required for recruitment of mTORC2 components to the rafts and Akt activation.

The possibility of reconstituting the damaged heart has introduced a new paradigm in cardiovascular biology and created the potential for a new therapeutic approach in the cardiovascular field, where there is a compelling need for innovative treatments. While the results of animal and early clinical studies are encouraging, the more direct use of cell-based therapies in patients is still long-reached. Gaps in our basic understanding of mechanisms, lack of important randomized, double blind, and controlled clinical trials, as well as technology development for cell production are among challenges to be overcome before full translation of cell based therapies in clinical arena. This review focuses on summarizing the latest knowledge in stem cell therapy for cardiovascular diseases.

BACKGROUND Electronic health records (EHRs) offer the opportunity to transform quality improvement by using clinical data for comparing hospital performance without the burden of chart abstraction. However, current performance measures using EHRs are lacking. METHODS With support from the Centers for Medicare & Medicaid Services (CMS), we developed an outcome measure of hospital risk-standardized 30-day mortality rates for patients with acute myocardial infarction for use with EHR data. As no appropriate source of EHR data are currently available, we merged clinical registry data from the Action Registry-Get With The Guidelines with claims data from CMS to develop the risk model (2009 data for development, 2010 data for validation). We selected candidate variables that could be feasibly extracted from current EHRs and do not require changes to standard clinical practice or data collection. We used logistic regression with stepwise selection and bootstrapping simulation for model development. RESULTS The final risk model included 5 variables available on presentation: age, heart rate, systolic blood pressure, troponin ratio, and creatinine level. The area under the receiver operating characteristic curve was 0.78. Hospital risk-standardized mortality rates ranged from 9.6% to 13.1%, with a median of 10.7%. The odds of mortality for a high-mortality hospital (+1 SD) were 1.37 times those for a low-mortality hospital (-1 SD). CONCLUSIONS This measure represents the first outcome measure endorsed by the National Quality Forum for public reporting of hospital quality based on clinical data in the EHR. By being compatible with current clinical practice and existing EHR systems, this measure is a model for future quality improvement measures.

Protein kinase Balpha (PKBalpha/Akt-1) is a key mediator of multiple signaling pathways involved in angiogenesis, cell proliferation and apoptosis among others. The unphosphorylated form of Akt-1 is virtually inactive and its full activation requires two phosphatidylinositol-3,4,5-triphosphate-dependent phosphorylation events, Thr308 by 3-phosphoinositide-dependent kinase-1 (PDK1) and Ser473 by an undefined kinase that has been termed PDK2. Recent studies have suggested that the Ser473 kinase is a plasma membrane raft-associated kinase. In this study we show that protein kinase Calpha (PKCalpha) translocates to the membrane rafts in response to insulin growth factor-1 (IGF-1) stimulation. Overexpression of PKCalpha increases Ser473 phosphorylation and Akt-1 activity, while inhibition of its activity or expression decreases IGF-1-dependent activation of Akt-1. Furthermore, in vitro, in the presence of phospholipids and calcium, PKCalpha directly phosphorylates Akt-1 at the Ser473 site. We conclude, therefore, that PKCalpha regulates Akt-1 activity via Ser473 phosphorylation and may function as PDK2 in endothelial cells.

Background— Prior claims analyses suggest that the use of intravenous inotropic therapy for patients hospitalized with heart failure varies substantially by hospital. Whether differences in the clinical characteristics of the patients explain observed differences in the use of inotropic therapy is not known. Methods and Results— We sought to characterize institutional variation in inotrope use among patients hospitalized with heart failure before and after accounting for clinical factors of patients. Hierarchical generalized linear regression models estimated risk-standardized hospital-level rates of inotrope use within 209 hospitals participating in Get With The Guidelines-Heart Failure (GWTG-HF) registry between 2005 and 2011. The association between risk-standardized rates of inotrope use and clinical outcomes was determined. Overall, an inotropic agent was administered in 7691 of 126 564 (6.1%) heart failure hospitalizations: dobutamine 43%, dopamine 24%, milrinone 17%, or a combination 16%. Patterns of inotrope use were stable during the 7-year study period. Use of inotropes varied significantly between hospitals even after accounting for patient and hospital characteristics (median risk-standardized hospital rate, 5.9%; interquartile range, 3.7%–8.6%; range, 1.3%–32.9%). After adjusting for case-mix and hospital structural differences, model intraclass correlation indicated that 21% of the observed variation in inotrope use was potentially attributable to random hospital effects (ie, institutional preferences). Hospitals with higher risk-standardized inotrope use had modestly longer risk-standardized length of stay ( P =0.005) but had no difference in risk-standardized inpatient mortality ( P =0.12) Conclusions— Use of intravenous inotropic agents during hospitalization for heart failure varies significantly among US hospitals even after accounting for patient and hospital factors.

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that is upregulated during exposure to hypoxia. In this study, we analyzed heart and lung VEGF mRNA expression and examined pulmonary vascular remodeling as well as myocardial capillary density in two rat models of pulmonary hypertension involving exposure to chronic hypoxia (CH) and treatment with monocrotaline (MCT), respectively. The rats were studied after 0.5, 1, 3, 15, and 30 days of exposure to 10% O2 or 1, 6, and 30 days after a subcutaneous MCT injection (60 mg/kg). Both CH and MCT induced pulmonary hypertension and hypertrophy of the right ventricle (RV) with increased RV weight and atrial natriuretic peptide mRNA expression. VEGF mRNA expression as assessed by Northern blot analysis was potently induced after 12 h of hypoxia in both the right and left ventricles. After prolonged exposure to hypoxia, VEGF mRNA returned to baseline in the left ventricle (LV) but remained increased in the RV, where it peaked after 30 days. In MCT rats, VEGF mRNA was unchanged in the LV but decreased by 50% in the RV and by 90% in the lungs after 30 days. VEGF mRNA remained unchanged in the lungs from CH rats. Pulmonary vascular remodeling was more pronounced in MCT than in CH rats. The number of capillaries per RV myocyte was increased in rats exposed to 30 days of hypoxia, whereas it remained unchanged in MCT rats despite a similar degree of RV hypertrophy. Our results suggest that the sustained increase in VEGF expression in the hypertrophied RV during CH may account for the increased number of capillaries per myocyte. In contrast, reduced VEGF expression in the lungs and RV of MCT rats may aggravate pulmonary vascular remodeling and compromise RV myocardial perfusion.

Bradykinin activity could explain the blood pressure increase during NaCl loading in hypertensive animals, but its contribution on vascular structure was not evaluated. We determined cardiac mass and large artery structure after a chronic, 4-mo, high-salt diet in combination with bradykinin B2-receptor blockade by Hoe-140. Four-week-old rats were divided into eight groups according to strain [spontaneously hypertensive rats (SHR) vs. Wistar-Kyoto (WKY) rats], diet (0.4 vs. 7% NaCl), and treatment (Hoe-140 vs. placebo). In WKY rats, a high-salt diet significantly increased intra-arterial blood pressure with minor changes in arterial structure independently of Hoe-140. In SHR, blood pressure remained stable but 1) the high-salt diet was significantly associated with cardiovascular hypertrophy and increased arterial elastin and collagen, and 2) Hoe-140 alone induced carotid hypertrophy. A high-salt diet plus Hoe-140 acted synergistically on carotid hypertrophy and elastin content in SHR, suggesting that the role of endogenous bradykinin on arterial structure was amplified in the presence of a high-salt diet.

The authors developed 8 measures of waste associated with cardiac procedures to assist hospitals in comparing their performance with peer facilities. Measure selection was based on review of the research literature, clinical guidelines, and consultation with key stakeholders. Development and validation used the data from 261 hospitals in a split-sample design. Measures were risk adjusted using Premier’s CareScience methodologies or mean peer value based on Medicare Severity Diagnosis-Related Group assignment. High variability was found in resource utilization across facilities. Validation of the measures using item-to-total correlations (range = 0.27-0.78), Cronbach α (.88), and Spearman rank correlation (0.92) showed high reliability and discriminatory power. Because of the level of variability observed among hospitals, this study suggests that there is opportunity for facilities to design successful waste reduction programs targeting cardiac-device procedures.

This study sought to determine hospital patterns of change in use of nesiritide over a 6-year period after publications of safety concerns in 2005 and to identify hospital characteristics associated with these patterns.The changing nature of medical evidence often requires a change in practice. Nesiritide was commercialized in 2001 for early relief of dyspnea in patients with decompensated heart failure. In 2005, concerns about its safety led to recommendations to restrict its use. Little is known about how hospitals responded to this information.We analyzed data from the Premier database, including 403 hospitals contributing 813,783 hospitalizations with heart failure from 2005 to 2010. We applied a growth mixture modeling approach to hospital-level, risk-standardized, quarterly use rates of nesiritide to distinguish hospital groups on the basis of their patterns of change in use.The proportion of hospitalizations using nesiritide declined from 15.4% in 2005 to 1.2% in 2010. The level and speed of change varied markedly among hospitals. After adjusting for differences in patient characteristics across hospitals and years, we identified 3 distinct groups of hospitals: "low users," "fast de-adopters," and "slow de-adopters." In multivariate regression analysis, these groups did not differ in traditional hospital characteristics, such as size, urban setting, or teaching status.We identified 3 distinct hospital groups characterized by their patterns of change in nesiritide use. These trajectory curves can provide hospitals with important feedback on how fast and effectively they react to new information compared with other hospitals. Uncovering factors that promote organizational learning requires further research.

Objectives The main objective of this study was to examine the relations between chloroguanide (proguanil) and mephenytoin metabolic ratios to determine whether or not chloroguanide could replace mephenytoin as a probe for the indirect in vivo measurement of CYP2C19 activity. An additional objective was to examine the interactions between chloroguanide, omeprazole, and mephenytoin, which are three substrates of CYP2C19. Methods Twenty healthy volunteers received 200 mg chloroguanide orally on three separate occasions in an open, randomized-sequence crossover design: once alone, once 2 hours before the oral administration of 100 mg mephenytoin, and once after oral administration for 7 days of 40 mg/day omeprazole. During one additional period, 100 mg mephenytoin was administered orally. The chloroguanide to cycloguanil ratio was determined in plasma 4 hours after drug administration; it was determined in urine collected over 4, 8, and 24 hours. The mephenytoin hydroxylation index was also measured in urine. Results All subjects were extensive metabolizers of chloroguanide and mephenytoin. We found no correlation between the mephenytoin hydroxylation index and the chloroguanide to cycloguanil ratio in any of the urine samples collected or in plasma. In the presence of chloroguanide, mephenytoin hydroxylation index increased from a baseline value of 1.2 ± 0.2 to 1.7 ± 1.0 (p < 0.05). In the presence of omeprazole, the chloroguanide to cycloguanil metabolic ratio in 24-hour urine increased from 2.2 ± 1.0 to 5.6 ± 3.2 (p < .001). Conclusion Chloroguanide inhibits the CYP2C19-dependent 4′-hydroxylation of mephenytoin. The bioactivation of chloroguanide to cycloguanil is inhibited by the CYP2C19 substrate omeprazole. However, the chloroguanide to cycloguanil metabolic ratio does not reflect the same array of S-mephenytoin hydroxylase activities found in extensive metabolizers as that shown by the mephenytoin hydroxylation index. Clinical Pharmacology & Therapeutics (1995) 58, 257–263; doi

BACKGROUND Because relative value unit (RVU)-based costs vary across hospitals, it is difficult to use them to compare hospital utilization. OBJECTIVE To compare estimates of hospital utilization using RVU-based costs and standardized costs. DESIGN Retrospective cohort. SETTING AND PATIENTS Years 2009 to 2010 heart failure hospitalizations in a large, detailed hospital billing database that contains an itemized log of costs incurred during hospitalization. INTERVENTION We assigned every item in the database with a standardized cost that was consistent for that item across all hospitals. MEASUREMENTS Standardized costs of hospitalization versus RVU-based costs of hospitalization. RESULTS We identified 234 hospitals with 165,647 heart failure hospitalizations. We observed variation in the RVU-based cost for a uniform “basket of goods” (10th percentile cost $1,552; 90th percentile cost of $3,967). The interquartile ratio (Q75/Q25) of the RVU-based costs of a hospitalization was 1.35 but fell to 1.26 after costs were standardized, suggesting that the use of standardized costs can reduce the “noise” due to differences in overhead and other fixed costs. Forty-six (20%) hospitals had reported costs of hospitalizations exceeding standardized costs (indicating that reported costs inflated apparent utilization); 42 hospitals (17%) had reported costs that were less than standardized costs (indicating that reported costs underestimated utilization). CONCLUSIONS Standardized costs are a novel method for comparing utilization across hospitals and reduce variation observed with RVU-based costs. They have the potential to help hospitals understand how they use resources compared to their peers and will facilitate research comparing the effectiveness of higher and lower utilization. Journal of Hospital Medicine 2013;8:373–379. © 2013 Society of Hospital Medicine

Background: Although loop diuretics are frequently used for patients with heart failure (HF), little is known about the variation in patterns of diuretic therapy in US hospitals. We sought to describe such treatment patterns among a diverse group of hospitals. Methods: We studied HF hospitalizations occurring during 2009-10 in Premier Inc. hospitals participating in a collaborative project to pool administrative and charge data, which includes information about drug types, average daily dose, and duration of therapy. We excluded hospitals with less than 25 HF hospitalizations. For ease of comparison, all diuretic doses were converted to bioequivalent doses of intravenous (IV) furosemide: 40mg IV furosemide ∼ 80mg oral furosemide ∼ 20mg (oral or IV) torsemide ∼ 1mg (oral or IV) bumetanide. Summary statistics were calculated. Results: Among 366 studied hospitals (264,675 HF hospitalizations), use of any loop diuretic had an interquartile range (IQR) from 92% to 96% (median: 94%). At the hospital level, the average daily dose IQR varied from 45mg to 64 mg (median: 55 mg) and the median duration of therapy was 4 days (IQR: 4 to 4; median: 4), as was the median length of stay. The IQR for use of furosemide varied from 89% to 94% (median: 92%), and its median average daily dose had an IQR from 40mg to 60 mg (median: 53 mg). Hospital use of bumetanide had an IQR from 2% to 11%, and hospital use of torsemide had an IQR from 0% to 4% (medians of 5% and 1%, respectively). The variation in median average daily dose for bumetanide and torsemide was greater than for furosemide (bumetanide IQR: 79mg to 127 mg, with median of 89 mg; torsemide IQR: 53mg to 120 mg, with median of 80 mg). Use of IV diuretics on the last day before home discharge had an IQR from 16% to 33% (median: 24%) across hospitals. Conclusion: US hospitals administer loop diuretics, particularly furosemide, to the vast majority of HF inpatients. The duration and daily dosage of therapy was similar across most hospitals. In contrast, a minority of hospitals used bumetanide and torsemide for several patients. The daily dosage of these agents showed more marked variation. We observed a high rate of intravenous diuretic use on the last day of hospitalization, with considerable variation across hospitals.

The possibility of reconstituting the damaged heart has introduced a new paradigm in cardiovascular biology and created the potential for a new therapeutic approach in the cardiovascular field, where there is a compelling need for innovative treatments. While the results of animal and early clinical studies are encouraging, the more direct use of cell-based therapies in patients is still long-reached. Gaps in our basic understanding of mechanisms, lack of important randomized, double blind, and controlled clinical trials, as well as technology development for cell production are among challenges to be overcome before full translation of cell based therapies in clinical arena. This review focuses on summarizing the latest knowledge in stem cell therapy for cardiovascular diseases.

To the Editor: Diuretics are a mainstay of treatment in both chronic and acute decompensated heart failure (HF). Studies during the 1990s and early 2000s show that roughly 90% of HF patients receive at least 1 class of diuretics, particularly a loop diuretic, for management of chronic ([1,2][1]) or

We report a case of acute myocardial infarction occurring in a patient with severe aortic stenosis and left ventricular hypertrophy. A coronary angiogram performed during the acute phase of evolving myocardial infarction excluded coronary obstruction as the cause of acute myocardial infarction in this patient.

Existing publicly reported readmission measures are condition-specific, representing less than 20% of adult hospitalizations. An all-condition measure may better measure quality and promote innovation.To develop an all-condition, hospital-wide readmission measure.Measure development study.4821 U.S. hospitals.Medicare fee-for-service beneficiaries aged 65 years or older.Hospital-level, risk-standardized unplanned readmissions within 30 days of discharge. The measure uses Medicare fee-for-service claims and is a composite of 5 specialty-based, risk-standardized rates for medicine, surgery/gynecology, cardiorespiratory, cardiovascular, and neurology cohorts. The 2007-2008 admissions were randomly split for development and validation. Models were adjusted for age, principal diagnosis, and comorbid conditions. Calibration in Medicare and all-payer data was examined, and hospital rankings in the development and validation samples were compared.The development data set contained 8 018 949 admissions associated with 1 276 165 unplanned readmissions (15.9%). The median hospital risk-standardized unplanned readmission rate was 15.8 (range, 11.6 to 21.9). The 5 specialty cohort models accurately predicted readmission risk in both Medicare and all-payer data sets for average-risk patients but slightly overestimated readmission risk at the extremes. Overall hospital risk-standardized readmission rates did not differ statistically in the split samples (P = 0.71 for difference in rank), and 76% of hospitals' validation-set rankings were within 2 deciles of the development rank (24% were more than 2 deciles). Of hospitals ranking in the top or bottom deciles, 90% remained within 2 deciles (10% were more than 2 deciles) and 82% remained within 1 decile (18% were more than 1 decile).Risk adjustment was limited to that available in claims data.A claims-based, hospital-wide unplanned readmission measure for profiling hospitals produced reasonably consistent results in different data sets and was similarly calibrated in both Medicare and all-payer data.Centers for MedicareMedicaid Services.

Chronic hypoxic pulmonary hypertension (PH) is associated with vasoconstriction and structural remodeling of pulmonary vessels including narrowing of the arterial lumen and loss of distal functional arteries. To test whether lung overexpression of the angiogenic factor vascular endothelial growth factor (VEGF) is beneficial in hypoxic PH, recombinant adenovirus encoding the human VEGF 165 gene under the control of a cytomegalovirus promoter (Ad. VEGF) or control vector containing no gene in the expression cassette (Ad.Null) was administered intratracheally to rats. With Ad. VEGF (10(8) plaque-forming units [pfu]), VEGF protein was present in bronchoalveolar lavage fluid as early as 2 d and until 17 d after gene transfer, but was not detected in serum. Only small patchy areas of mononuclear cells without cell damage, edema, or hemorrhage were observed on lung histology with no significant change in lung permeability. In rats pretreated with Ad.VEGF (10(8) pfu) 2 d before a 2-wk exposure to hypoxia (10% O(2)), lower values versus Ad. Null-pretreated controls were found for pulmonary artery pressure (25 +/- 1 versus 30 +/- 2 mm Hg, P < 0.05), right ventricular over left ventricular-plus-septum weight (0.37 +/- 0.01 versus 0.47 +/- 0. 02, P < 0.001), normalized wall thickness of 50- to 200-microm vessels (P < 0.001), and muscularization of distal vessels (P < 0. 001). Pretreatment with Ad.VEGF (10(8) pfu) increased endothelial nitric oxide synthase activity in lung tissue and partially restored endothelium-dependent vasodilation in isolated lungs from chronically hypoxic rats, as assessed by improvement of ionophore A23187-induced vasodilation and attenuation of endothelin-1 (300 pmol)-induced vasoconstriction, an effect abolished in the presence of nitro-L-arginine methylester. We conclude that adenoviral-mediated VEGF overexpression in the lungs attenuates development of hypoxic PH, in part by protecting endothelium-dependent function.

International audience; Focal vascular injury and impaired endothelial function are features of pulmonary hypertension (PH) that lead to enhanced platelet endothelial cell interactions. Vascular endothelial growth factor (VEGF) is contained in platelets and released at sites of vascular injury to promote endothelial repair and wound healing in combination with platelet-derived nonspecific mitogens such as platelet-derived growth factor (PDGF). The overall balance between platelet VEGF and PDGF was investigated in 21 patients with primary PH, 8 with secondary PH, and 27 with chronic hypoxemic lung disease (CHLD), as well as in 29 control subjects. Platelet VEGF content was increased in patients with primary and secondary PH as compared with control subjects (518 +/- 89, 675 +/- 156, and 166 +/- 29 fg/10(5) platelets, respectively; p < 0.01), whereas platelet PDGF content was similar in the three groups (31 +/- 2, 36 +/- 4, and 33 +/- 3 pg/10(5) platelets, respectively; NS). Patients treated with a continuous prostacyclin infusion had a higher platelet VEGF but a similar platelet PDGF content as compared with untreated patients. Moderate increases in platelet VEGF and PDGF contents were observed in the CHLD patients. We conclude that patients with primary or secondary PH have an increase in platelet VEGF content, but not in platelet PDGF content, and that their platelet VEGF content increases further in response to prostacyclin infusion. We suggest that imbalance between platelet VEGF and PDGF is beneficial to patients with PH.

The onset of tissue ischemia is associated with significant changes in the expression of heparan sulfate- (HS) carrying core proteins that, in turn, lead to alterations in composition of the extracellular HS matrix. Since HS can bind numerous growth factors and cytokines, such changes in the HS matrix content can have profound effects on the ability of these factors to interact with their target cells. To investigate the role of increased HS matrix content on microvascular function, we used alpha-myosin heavy chain (MHC) promoter to overexpress a HS-carrying core protein, syndecan-4, in cardiac myocytes in mice. Mice expressing the transgene (alpha MHC-S4) demonstrated a significant increase in nitric oxide (NO) release in the coronary effluent in response to fibroblast growth factor 2 (FGF2, 1 microg/mL) administration despite similar expression levels of NO synthase genes II and III (iNOS and eNOS, respectively). In vitro studies of coronary microvessels derived from alpha MHC-S4 mice demonstrated increased relaxation response to FGF2 compared to control mice. At the same time, vasodilator response to adenosine diphosphate (ADP) was significantly impaired in alpha MHC-S4 mice-derived microvessels. Addition of exogenous HS to microvessels derived from control mice enhanced FGF2-induced vasodilation while inhibiting ADP-induced vasomotion. The vasomotor activity of the endothelial receptor-independent agent (A23187) and the endothelium-independent agent (sodium nitroprusside) was not affected by heparan sulfate. These results demonstrate that alterations in HS production have a profound and heterogeneous effect on endothelial receptor-dependent vasodilators and point to a novel role of the HS matrix in regulation of microvascular homeostasis.

Le systeme cardiovasculaire represente un domaine d'application de la therapie genique a court et a moyen terme, notamment en ce qui concerne le traitement des complications de la maladie atheromateuse. Les progres les plus avances concernent la stimulation de l'angiogenese au cours des maladies ischemiques. L'amelioration fonctionnelle et clinique obtenue recemment apres transfert du gene du VEGF (vascular endothelial growth factor) chez des patients atteints d'arterite ischemique des membres inferieurs offre de nouvelles perspectives therapeutiques. Le transfert de gene utilise dans le traitement de la restenose postangioplastie reste a l'heure actuelle prometteur malgre l'absence d'application clinique. Les mises en pratique de la therapie genique a d'autres problematiques cardiovasculaires apparaissent plus lointaines, conditionnees par une meilleure connaissance des mecanismes physiopathologiques ainsi que par l'amelioration des techniques de transfert de gene.

Syndecan-4 is one of the principal heparan sulfate-carrying proteins on the cell surface. Unlike other members of syndecan family, syndecan-4 mediates phosphatidylinositol 4,5-bisphosphate 2 (PIP2)-dependent PKC-α activation, and overexpression of syndecan-4 in vitro results in enhanced FGF2 signaling. The present study was designed to test the functional effect of increased syndecan-4 expression in endothelial cells in transgenic mice. Several transgenic mice lines expressing syndecan-4 cDNA under control of human endothelial nitric oxide (NO) synthase (eNOS) promoter were generated. Exogenous syndecan-4 was mainly expressed in the heart, brain, and lungs. In particular, the heart demonstrated the greatest increase in the ratio of transgenic-to-native syndecan-4 gene expression. Vessels from the eNOS-syndecan-4 mice demonstrated more pronounced vasodilation to FGF2 but not to VEGF-A165, sodium nitroprusside, and A 23187 compared with wild-type mice. To elucidate the mechanism of this effect, we measured NO release from primary cardiac endothelial cells isolated from transgenic or wild-type adult mice. Cells from the eNOS-syndecan-4 transgenic mice had a significant increase in FGF2- and VEGF-A165-induced NO release compared with endothelial cells from the wild-type mice. However, the absolute magnitude of this increase was higher for FGF2 than VEGF-A165. In conclusion, enhanced syndecan-4 expression in mouse cardiac endothelial cells results in preferential augmentation of FGF2 but not VEGF-A165-induced NO release.