A multi-stem cell basis for craniosynostosis and calvarial mineralization.

Craniosynostosis is a group of disorders of premature calvarial suture fusion. The identity of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts in craniosynostosis remains poorly understood. Here we show that both physiologic calvarial mineralization and pathologic calvarial fusion in craniosynostosis reflect the interaction of two separate stem cell lineages; a previously identified cathepsin K (CTSK) lineage CSC1 (CTSK+ CSC) and a separate discoidin domain-containing receptor 2 (DDR2) lineage stem cell (DDR2+ CSC) that we identified in this study. Deletion of Twist1, a gene associated with craniosynostosis in humans2,3, solely in CTSK+ CSCs is sufficient to drive craniosynostosis in mice, but the sites that are destined to fuse exhibit an unexpected depletion of CTSK+ CSCs and a corresponding expansion of DDR2+ CSCs, with DDR2+ CSC expansion being a direct maladaptive response to CTSK+ CSC depletion. DDR2+ CSCs display full stemness features, and our results establish the presence of two distinct stem cell lineages in the sutures, with both populations contributing to physiologic calvarial mineralization. DDR2+ CSCs mediate a distinct form of endochondral ossification without the typical haematopoietic marrow formation. Implantation of DDR2+ CSCs into suture sites is sufficient to induce fusion, and this phenotype was prevented by co-transplantation of CTSK+ CSCs. Finally, the human counterparts of DDR2+ CSCs and CTSK+ CSCs display conserved functional properties in xenograft assays. The interaction between these two stem cell populations provides a new biologic interface for the modulation of calvarial mineralization and suture patency.

Nutritional management of heart failure.

Nutrition in the cardiovascular field to date has focused on improving lifestyle-related diseases such as hypertension and diabetes from the viewpoint of secondary prevention. For these conditions, "nutrition for weight loss" is recommended, and nutritional guidance that restricts calories is provided. On the other hand, in symptomatic Stage C and D heart failure, it is known that underweight patients who manifest poor nutrition, sarcopenia, and cardiac cachexia have a poor prognosis. This is referred to as the "Obesity paradox". In order to "avoid weight loss" in patients with heart failure, a paradigm shift to nutritional management to prevent weight loss is needed. Rather than prescribing uniform recommendation for salt reduction of 6 g/day or less, awareness of the behavior change stage model is attracting attention. In this setting, the value of salt restriction will need to be determined to determine the priority level of intervention for undernutrition versus the need to prevent congestive signs and symptoms. In the Intensive Care Unit (ICU)/Cardiac Care Unit (CCU) for acute heart failure, nutritional intervention should be considered within 48 h of admission. Key points are selection of access route, timing of intervention, and monitoring of side effects. In nutritional management at home and in end-of-life care, food is a reflection of an individual's values, as well as a source of joy and encouragement. The importance of digestive tract should also be recognized in heart failure from oral flail to intestinal edema, constipation, and the intestinal bacteria called the heart-gut axis. Finally, we would like to propose a new term "heart nutrition" for nutritional management in patients with heart failure in this review. Compared to the evidence for exercise therapy in heart failure, studies assessing nutritional management remain scarce and there is a need for research in this area in the future.

Systemic Inflammation and Cognitive Decrements in Patients With Stage B Heart Failure.

OBJECTIVE: This study aimed to investigate the role of systemic inflammation in reduced cognitive functioning in patients with early-stage heart failure (HF) while determining associations with other cardiovascular risk factors. METHODS: Patients with stage B HF (n = 270; mean [standard deviation] age = 66.1 [10.1] years) were examined cross-sectionally for relationships among cardiovascular disease (CVD) and psychological risk factors, C-reactive protein (CRP), and Montreal Cognitive Assessment (MoCA) scores. A subsample (n = 83) at high risk for stage C HF (B-type natriuretic peptide levels ≥65 pg/ml) were followed up for 12 months for relationships between CRP levels and cognitive function. RESULTS: Baseline smoking (χ2 = 6.33), unmarried (χ2 = 12.0), hypertension (χ2 = 5.72), greater body mass index (d = 0.45), and physical fatigue (d = 0.25) were related to higher CRP levels (p values < .05). Cross-sectionally, CRP levels were negatively related to MoCA scores, beyond CVD (ΔR2 = 0.022, ß = -0.170, p < .010) and psychological risk factors (ΔR2 = 0.016, ß = 0.145, p < .027), and related to mild cognitive impairment criteria (odds ratio = 1.35, 95% confidence interval [CI] = 1.00-1.81, p = .046). Across 12 months, B-type natriuretic peptide high-risk patients with CRP levels ≥3 mg/L had lower MoCA scores (23.6; 95% CI = 22.4-24.8) than did patients with CRP levels <3 mg/L (25.4; 95% CI = 24.4-26.5; p = .024). CONCLUSIONS: Patients with stage B HF and heightened CRP levels had greater cognitive impairment at baseline and follow-up, independent of CVD and potentially psychological risk factors. Low-grade systemic inflammation may be one mechanism involved in cognitive dysfunction at early stages of HF.

Depressive symptoms in asymptomatic stage B heart failure with Type II diabetic mellitus.

BACKGROUND: The presence of concomitant Type II diabetic mellitus (T2DM) and depressive symptoms adversely affects individuals with symptomatic heart failure (HF). HYPOTHESIS: In presymptomatic stage B HF, this study hypothesized the presence of greater inflammation and depressive symptoms in T2DM as compared to non-T2DM Stage B patients. METHODS: This cross-sectional study examined clinical parameters, inflammatory biomarkers, and depressive symptoms in 349 T2DM and non-T2DM men with asymptomatic stage B HF (mean age 66.4 years ±10.1; range 30-91). RESULTS: Fewer diabetic HF patients had left ventricular (LV) systolic dysfunction (P < .05) although more had LV diastolic dysfunction (P < .001). A higher percentage of T2DM HF patients were taking ACE-inhibitors, beta-blockers, calcium channel blockers, statins, and diuretics (P values < .05). T2DM HF patients had higher circulating levels of interleukin-6 (IL-6) (P < .01), tumor necrosis factor-alpha (P < .01), and soluble ST2 (sST2) (P < .01) and reported more somatic/affective depressive symptoms (Beck Depression Inventory II) (P < .05) but not cognitive/affective depressive symptoms (P = .20). Among all patients, in a multiple regression analysis predicting presence of somatic/affective depressive symptoms, sST2 (P = .026), IL-6 (P = .010), B-type natriuretic peptide (P = .016), and sleep (Pittsburgh Sleep Quality Index [P < .001]) were significant predictors (overall model F = 15.39, P < .001, adjusted R2 = .207). CONCLUSIONS: Somatic/affective but not cognitive/affective depressive symptoms are elevated in asymptomatic HF patients with T2DM patients. Linkages with elevated inflammatory and cardiac relevant biomarkers suggest shared pathophysiological mechanisms among T2DM HF patients with somatic depression, and these conditions are responsive to routine interventions, including behavioral. Copyright © 2019 John Wiley & Sons, Ltd.

Which advanced heart failure therapy strategy is optimal for patients over 60 years old?

BACKGROUND: The optimal advanced heart failure (HF) therapy strategy for patients aged 60 or older with end-stage HF refractory to optimal medical therapy remains uncertain. This study compares outcomes of three advanced HF therapy strategies in this patient population. METHODS: A single-center retrospective study was conducted in 95 patients aged 60-73 years who had undergone isolated heart transplantation (HTx) or continuous flow left ventricular assist device (LVAD) implantation from 2010 to 2017. Patients were stratified into three cohorts by strategy; HTx-only (N.=25), LVAD-to-HTx (N.=29), and LVAD-only (N.=41). Primary end point was 2-year overall survival. Secondary end points included incidence of post-operative adverse events, freedom from first readmission at 1 year, and percentage of days spent in hospital following advanced HF therapy. RESULTS: Two-year survival was 91% in HTx-only patients, 88% in LVAD-to-HTx patients, and 49% in LVAD-only patients (P=0.0008). No significant difference in post-transplant survival was found between patients with or without LVAD-related adverse events preceding transplantation (P=0.42). One-year freedom from first readmission was 38.3% in HTx-only patients, 17.2% in LVAD-to-HTx patients and 7.3% in LVAD-only patients (P=0.0028). Patients in LVAD-to-HTx cohort had higher incidences of gastrointestinal bleeding (38% vs. 3%; P<0.01), major bleeding (28% vs. 3%; P=0.02), and right heart failure (69% vs. 31%; P<0.01) during post-LVAD period compared with post-HTx period. Their percentage of days spent in hospital during post-LVAD period was significantly higher than post-HTx period (7.9% vs. 1.2%; P<0.001). CONCLUSIONS: Our experience with patients over 60 years old undergoing advanced therapy suggests that HTx-only and LVAD-to-HTx strategies had superior medium-term survival than LVAD-only strategy. LVAD-to-HTx strategy is effective in reducing incidence of adverse events and percentage of hospitalized days in this specific patient population.

A multimarker multi-time point-based risk stratification strategy in acute heart failure: results from the RELAX-AHF trial.

AIMS: We evaluated the added prognostic value of a multi-time point-based multimarker panel of biomarkers in patients with acute heart failure (AHF). METHODS AND RESULTS: Seven circulating biomarkers [NT-proBNP, high sensitivity cardiac troponin T (hs-cTnT), soluble ST2 (sST2), growth differentiation factor 15 (GDF-15), cystatin-C, galectin-3, and high sensitivity C-reactive protein (hs-CRP)] were measured at baseline and on days 2, 5, 14, and 60 in 1161 patients enrolled in the RELAX-AHF trial. Patients with BNP ≥350 ng/L or NT-proBNP ≥1400 ng/L, mild to moderate renal impairment, and systolic blood pressure >125 mmHg were included in the trial. Time-dependent Cox regression analysis was utilized to evaluate the incremental value of serial measurement of biomarkers. Added value of individual biomarkers and their combination, on top of a pre-specified baseline model, was quantified with the gain in the C-index. Serial biomarker evaluation showed incremental predictive value over baseline measurements alone for the prediction of 180-day cardiovascular mortality except for galectin-3. While a repeat measurement as early as day 2 was adequate for NT-proBNP and cystatin-C in terms of maximizing discriminatory accuracy, further measurements on days 14 and 60 provided added value for hs-cTnT, GDF-15, sST2, and hs-CRP. Individual biomarker additions on top of the baseline model showed additional prognostic value. The greatest prognostic gain was, however, attained with the combination of NT-proBNP, hs-cTnT, GDF-15, and sST2, which yielded 0.08 unit absolute increment in the C-index to 0.87 (95% confidence interval 0.83-0.91]. CONCLUSION: In patients with AHF and mild to moderate renal impairment, a multimarker approach based on a panel of serially evaluated biomarkers provides the greatest prognostic improvement unmatched by a single time point-based single marker strategy.

Effects of serelaxin in acute heart failure patients with renal impairment: results from RELAX-AHF.

BACKGROUND: Serelaxin showed beneficial effects on clinical outcome and trajectories of renal markers in patients with acute heart failure. We aimed to study the interaction between renal function and the treatment effect of serelaxin. METHODS: In the current post hoc analysis of the RELAX-AHF trial, we included all patients with available estimated glomerular filtration rate (eGFR) at baseline (n = 1132). Renal impairment was defined as an eGFR <60 ml/min/1.73 m(2) estimated by creatinine. RESULTS: 817 (72.2 %) patients had a baseline eGFR <60 ml/min/1.73 m(2). In placebo-treated patients, baseline renal impairment was related to a higher 180 day cardiovascular (HR 3.12, 95 % CI 1.33-7.30) and all-cause mortality (HR 2.81, 95 % CI 1.34-5.89). However, in serelaxin-treated patients, the risk of cardiovascular and all-cause mortality was less pronounced (HR 1.19, 95 % CI 0.54 -2.64; p for interaction = 0.106, and HR 1.15 95 % CI 0.56-2.34 respectively; p for interaction = 0.088). In patients with renal impairment, treatment with serelaxin resulted in a more pronounced all-cause mortality reduction (HR 0.53, 95 % CI 0.34-0.83), compared with patients without renal impairment (HR 1.30, 95 % CI 0.51-3.29). CONCLUSION: Renal dysfunction was associated with higher cardiovascular and all-cause mortality in placebo-treated patients, but not in serelaxin-treated patients. The observed reduction in (cardiovascular) mortality in RELAX-AHF was more pronounced in patients with renal dysfunction. These observations need to be confirmed in the ongoing RELAX-AHF-2 trial.

Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: results from the RELAX-AHF trial.

AIMS: Serelaxin is effective in relieving dyspnoea and improving multiple outcomes in acute heart failure (AHF). Many AHF patients have preserved ejection fraction (HFpEF). Given the lack of evidence-based therapies in this population, we evaluated the effects of serelaxin according to EF in RELAX-AHF trial. METHODS AND RESULTS: RELAX-AHF randomized 1161 AHF patients to 48-h serelaxin (30 µg/kg/day) or placebo within 16 h from presentation. We compared the effects of serelaxin on efficacy endpoints, safety endpoints, and biomarkers of organ damage between preserved (≥50%) and reduced (<50%, HFrEF) EF. HFpEF was present in 26% of patients. Serelaxin induced a similar dyspnoea relief in HFpEF vs. HFrEF patients by visual analogue scale-area under the curve (VAS-AUC) through Day 5 [mean change, 461 (-195, 1117) vs. 397 (10, 783) mm h, P = 0.87], but had possibly different effects on the proportion of patients with moderately or markedly dyspnoea improvement by Likert scale at 6, 12, and 24 h [odds ratio for favourable response, 1.70 (0.98, 2.95) vs. 0.85 (0.62, 1.15), interaction P = 0.030]. No differences were encountered in the effect of serelaxin on short- or long-term outcome between HFpEF and HFrEF patients including cardiovascular death or hospitalization for heart/renal failure through Day 60, cardiovascular death through Day 180, and all-cause death through Day 180. Similar safety and changes in biomarkers (high-sensitivity troponin T, cystatin-C, and alanine/aspartate aminotransferases) were found in both groups. CONCLUSIONS: In AHF patients with HFpEF compared with those with HFrEF, serelaxin was well tolerated and effective in relieving dyspnoea and had a similar effect on short- and long-term outcome, including survival improvement.

Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes.

OBJECTIVES: The aim of this study was to assess the effects of serelaxin on short-term changes in markers of organ damage and congestion and relate them to 180-day mortality in patients with acute heart failure. BACKGROUND: Hospitalization for acute heart failure is associated with high post-discharge mortality, and this may be related to organ damage. METHODS: The Pre-RELAX-AHF (Relaxin in Acute Heart Failure) phase II study and RELAX-AHF phase III study were international, multicenter, double-blind, placebo-controlled trials in which patients hospitalized for acute heart failure were randomized within 16 h to intravenous placebo or serelaxin. Each patient was followed daily to day 5 or discharge and at days 5, 14, and 60 after enrollment. Vital status was assessed through 180 days. In RELAX-AHF, laboratory evaluations were performed daily to day 5 and at day 14. Plasma levels of biomarkers were measured at baseline and days 2, 5, and 14. All-cause mortality was assessed as a safety endpoint in both studies. RESULTS: Serelaxin reduced 180-day mortality, with similar effects in the phase II and phase III studies (combined studies: N = 1,395; hazard ratio: 0.62; 95% confidence interval: 0.43 to 0.88; p = 0.0076). In RELAX-AHF, changes in markers of cardiac (high-sensitivity cardiac troponin T), renal (creatinine and cystatin-C), and hepatic (aspartate transaminase and alanine transaminase) damage and of decongestion (N-terminal pro-brain natriuretic peptide) at day 2 and worsening heart failure during admission were associated with 180-day mortality. Serelaxin administration improved these markers, consistent with the prevention of organ damage and faster decongestion. CONCLUSIONS: Early administration of serelaxin was associated with a reduction of 180-day mortality, and this occurred with fewer signs of organ damage and more rapid relief of congestion during the first days after admission.

Depression ratings and antidepressant use among outpatient heart failure patients: implications for the screening and treatment of depression.

OBJECTIVE: To investigate the characteristics of antidepressant use among heart failure (HF) outpatients. METHODS: Self-reported data on antidepressant use, Beck Depression Inventory (BDI) ratings, and demographics, as well as HF diagnosis severity, was collected from 218 New York Heart Association (NYHA) Classes I-IV HF outpatients (mean age 57.29 years). RESULTS: The overall prevalence of depressive symptoms (BDI > 10) was 43.1% (n = 94); 23.4% had a prior diagnosis of depression. Thirty-three percent of patients were taking antidepressants but, despite this treatment, 64% still showed at least mild-moderate depressive symptoms (BDI > or = 10) compared to 34% of patients not currently receiving antidepressants (p = 0.05). When asked if their mood had improved as a result of antidepressant therapy, 45% reported responses ranging from "halfway back to normal" to no improvement at all; BDI scores were related to self-reports of how well antidepressant therapy affected patient's mood (p < .01). Among patients receiving antidepressants (primarily SSRIs), 26% did not have a formal depression diagnosis prior to receiving antidepressants, and 39.1% reported never having had a dose adjustment in antidepressant medication. Similar numbers of patients were prescribed antidepressants by primary care physicians as mental health providers, while much fewer cardiologists prescribed antidepressants. CONCLUSIONS: Findings provide insight into practice and provider patterns related to antidepressant use in HF. HF patients treated with antidepressants still show high rates of depressed mood, and follow-up and monitoring of effectiveness of antidepressant therapy needs attention. Effective treatment of depression could support improved clinical outcomes and better quality of life for HF patients.

Circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1) independently predict depressive symptom severity after 12 months in heart failure patients.

OBJECTIVE: To determine whether inflammatory markers prospectively predict depressive symptom severity 12 months later in heart failure (HF) patients. METHODS: In 30 HF patients we assessed depressive symptom severity by the Beck depression inventory (BDI) at baseline as well as 12 months later. We measured circulating levels of the soluble intercellular adhesion molecule (sICAM)-1, the cytokine interleukin (IL)-6 and the acute phase protein C-reactive protein (CRP) at baseline assessment. RESULTS: sICAM-1 (r=.38, p=.045) but not CRP or IL-6 correlated with BDI scores 12 months later. Hierarchical linear regression analysis revealed that independent of baseline BDI assessment, cardiovascular risk factors, indicators of HF disease severity, and medication intake, sICAM-1 significantly predicted BDI scores 12 months later. sICAM-1 independently explained between 7% (beta=.26, p=.040) and 10% (beta=.35, p=.045) of the total variance in BDI scores 12 months later. CONCLUSION: The findings from this exploratory analysis suggest that the adhesion molecule sICAM-1 is an independent predictor of depressive symptoms 12 months later in HF patients. Our prospective findings support the suggested role for inflammation in increasing future depressive symptom severity and extend this linkage for the first time to HF.

Selective and specific regulation of ectodomain shedding of angiotensin-converting enzyme 2 by tumor necrosis factor alpha-converting enzyme.

Angiotensin-converting enzyme 2 (ACE2) is a newly identified regulator of the renin-angiotensin system. This type I membrane-anchored protein has a catalytically active ectodomain that undergoes shedding. Tumor necrosis factor alpha-converting enzyme (TACE) has been shown to be involved in ACE2 shedding. Although pathophysiological significance of ACE2 shedding has been suggested, regulation of this process by TACE is not clearly defined. We characterized TACE-mediated constitutive ectodomain shedding of ACE2 using wild-type Chinese Hamster Ovary (WT-CHO), the TACE-mutant M2 (M2-CHO) cells, and EC-4 and EC-2 cells that are fibroblasts from wild-type and TACE-null mice, respectively. ACE2 was constitutively cleaved to release two distinct major soluble forms. The deglycosylated molecular masses of the larger (LSF) and smaller soluble form (SSF) were approximately 80 and 70 kDa, respectively. These forms had equivalent enzyme activities. Reduced shedding for the LSF from M2-CHO and EC-2 cells when compared with WT-CHO and EC-4 cells, respectively, was noted. TACE reconstitution in EC-2 cells expressing ACE2 resulted in increase in LSF but not SSF release, demonstrating a main role of TACE in LSF release and distinct regulations of release of the two soluble forms. Deletions of the juxtamembrane region of ACE2 reduced LSF release in CHO cell lines, whereas it abolished TACE-induced shedding in EC-2 cells. Analysis of TACE structural domains confirmed that the active site in the catalytic domain is essential for ACE2 shedding but that noncatalytic domains also play additional roles. These results demonstrate selective and specific regulation of constitutive shedding of ACE2 by TACE.

A smoker's paradox in patients hospitalized for heart failure: findings from OPTIMIZE-HF.

AIMS: Cigarette smoking is a well-established risk factor for cardiovascular disease yet several studies have shown lower mortality after acute coronary syndromes in smokers compared with non-smokers, the so called 'smoker's paradox'. This study aimed to ascertain the relationship between smoking and clinical outcomes in patients hospitalized with heart failure (HF). METHODS AND RESULTS: OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) collected data on 48 612 patients from 259 hospitals. Characteristics, treatments, and outcomes were compared for current/recent smokers vs. those without current/recent smoking, and multivariable regression analyses with adjustment for hospital clustering were performed. There were 7743 (15.9%) smokers, 39 126 (80.5%) non-smokers, and 1743 (3.6%) missing. Smokers were younger, had similar renal function, but lower ejection fraction. The risk of in-hospital mortality was less in smokers (2.3 vs. 3.9%, P < 0.001). After extensive covariate adjustment, smokers still had lower in-hospital mortality risk OR (odds ratio) 0.70, 95% CI (confidence interval) 0.56-0.88, P = 0.002. Post-discharge, smokers (n = 998) had similar mortality risk (6.7 vs. 8.4%, P = 0.29) compared with those without current/recent smoking. CONCLUSION: Smokers hospitalized with HF had lower risk adjusted in-hospital mortality and similar early post-discharge mortality compared with non-smokers. The residual association of smoking and better prognosis, the 'smoker's paradox', was not fully explained by measured covariates.

Quality of care of and outcomes for African Americans hospitalized with heart failure: findings from the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure) registry.

OBJECTIVES: We sought to examine the characteristics, quality of care, and clinical outcomes for a large cohort of African-American patients hospitalized with heart failure (HF) in centers participating in a quality improvement initiative. BACKGROUND: Heart failure in African Americans is characterized by variations in natural history, lesser response to evidence-based therapies, and disparate health care. We hypothesized that a performance improvement program will achieve similar adherence to quality measures in African Americans admitted with HF compared with non-African Americans. METHODS: The OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure) registry-based performance-improvement program includes a pre-specified 10% subgroup with 60- to 90-day follow-up. Data on quality of care measures and outcomes were analyzed for 8,608 African-American patients compared with 38,501 non-African-American patients. RESULTS: African Americans were significantly younger and more likely to receive evidence-based medications but less likely to receive discharge instructions and smoking cessation counseling. In multivariable analyses, African-American race was an independent predictor of lower in-hospital mortality (odds ratio 0.71; 95% confidence interval 0.57 to 0.87; p < 0.001) but similar hospital length of stay. After multivariable adjustment, post-discharge outcomes were similar for American-American and non-African-American patients, but African-American race was associated with higher angiotensin-converting enzyme inhibitor prescription and left ventricular function assessment; no other HF quality indicators were influenced by race. CONCLUSIONS: In the context of a performance-improvement program, African Americans with HF received similar or better treatment with evidence-based medications, less discharge counseling, had better in-hospital survival, and similar adjusted risk of follow-up death/repeat hospital stay.

Improving the titer of recombinant adenovirus by suppressing problematic transgene transcription during packaging.

A new strategy to package "problematic" transgenes in adenovirus was developed that was based on modifications of the tetracycline-inducible system. This strategy used two components: the adenoviral genome containing the transgene under control of a hybrid TRE promoter/SV40 enhancer and a trans-encoded tTS suppressor Using luciferase reporters, expression of tTS in 293A cells reduced transcription from the promoter/enhancer 25-fold. Procaspase 8 adenovirus was then tested, since it is known to package poorly with standard adenoviral systems. Expression of tTS in 293A cells increased the titer of procaspase 8 adenovirus by 22-fold in initial viral packaging (using transiently transfected tTS) and 9-fold in subsequent viral reamplification (using 293A cells stably expressing tTS). The Tac antigen gene (i.e., CD25), which packages in adenovirus without difficulty, was also tested as a control. In contrast to that observed with procaspase 8, tTS expression did not alter the titer obtained when packaging the CD25 gene, thus excluding nonspecific effects of tTS expression on adenoviral titer Since tTS was provided in trans and did not package in the resulting adenoviruses, strong transcription of the transgenes occurred in transducted cells without the need of additional reagents.

Influence of a performance-improvement initiative on quality of care for patients hospitalized with heart failure: results of the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF).

BACKGROUND: Despite evidence-based national guidelines for optimal treatment of heart failure (HF), the quality of care remains inadequate. We sought to evaluate the effect of a national hospital-based initiative on quality of care in patients hospitalized with HF. METHODS: Two hundred fifty-nine US hospitals participating in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) submitted data on 48 612 patients with HF from March 1, 2003, through December 31, 2004. Admission, hospital, discharge care, and outcomes data were collected using a Web-based registry that provided real-time feedback on performance measures benchmarked to other hospitals. Process-of-care improvement tools, including evidence-based best-practice algorithms and customizable admission and discharge sets, were provided. RESULTS: Provision of complete discharge instructions and smoking-cessation counseling increased significantly (from 46.8%-66.5% and 48.2%-75.6%, respectively; P < .001 for both). Left ventricular function assessment started at a high rate (89.3%) and improved to 92.1% (P < .001). Angiotensin-converting enzyme inhibitors were prescribed at discharge to 75.8% of eligible patients, which did not improve during the 2-year study. There were trends for reduction of in-hospital mortality, postdischarge death, and combined postdischarge death and rehospitalization and a significant reduction in mean length of stay. Use of preprinted admission order sets and/or discharge checklists increased from 35.6% to 54.1% and was associated with an increase in the use of evidence-based therapies and lower risk-adjusted in-hospital mortality. CONCLUSIONS: Participation in OPTIMIZE-HF was associated with an increase in use of evidence-based therapy, adherence to performance measures, and shorter lengths of stay in patients hospitalized with HF. Increased use of process-of-care improvement tools was associated with further improvements in quality of care. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00344513.

Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects.

ANG-(1-7) improves the function of the remodeling heart. Although this peptide is generated directly within the myocardium, the effects of ANG-(1-7) on cardiac fibroblasts that play a critical role in cardiac remodeling are largely unknown. We tested the hypothesis that specific binding of ANG-(1-7) to cardiac fibroblasts regulates cellular functions that are involved in cardiac remodeling. 125I-labeled ANG-(1-7) binding assays identified specific binding sites of ANG-(1-7) on adult rat cardiac fibroblasts (ARCFs) with an affinity of 11.3 nM and a density of 131 fmol/mg protein. At nanomolar concentrations, ANG-(1-7) interacted with specific sites that were distinct from ANG II type 1 and type 2 receptors without increasing cytosolic Ca2+ concentration. At these concentrations, ANG-(1-7) had inhibitory effects on collagen synthesis as assessed by [3H]proline incorporation and decreased mRNA expression of growth factors in ARCFs. These effects of ANG-(1-7) contrasted with effects of ANG II. Pretreatment of ARCFs with ANG-(1-7) inhibited ANG II-induced increases in collagen synthesis and in mRNA expression of growth factors, including endothelin-1 and leukemia inhibitory factor. ANG-(1-7) pretreatment also inhibited the stimulatory effects of conditioned medium from ANG II-treated ARCFs on [3H]leucine incorporation and atrial natriuretic factor mRNA expression, markers of hypertrophy, in cardiomyocytes. Thus ANG-(1-7) interacted with specific receptors on ARCFs to exert potential antifibrotic and antitrophic effects that could reverse ANG II effects. These results suggest that ANG-(1-7) may play an important role in the heart in regulating cardiac remodeling.

Etanercept or intravenous immunoglobulin attenuates expression of genes involved in post-myocardial infarction remodeling.

OBJECTIVE: Persistently elevated levels of inflammatory cytokines such as tumor necrosis factor (TNF)alpha after acute myocardial infarction (MI) may contribute to maladaptive ventricular remodeling. The aim of the present study was to examine the effects of immunomodulatory therapy with recombinant soluble TNF receptor (TNFR:Fc) or intravenous immunoglobulin (IVIg) on left and right ventricular post-MI remodeling in rats. METHODS AND RESULTS: Adult male Sprague-Dawley rats were subjected to MI by left coronary artery ligation and randomized to treatment with vehicle, TNFR:Fc, or IVIg and sacrificed after 7 days. The main findings were that: (i) TNFR:Fc- and IVIg-treated rats developed less right ventricular (RV) hypertrophy compared to vehicle-treated controls. (ii) LV and arterial pressures in post-MI rats were not affected by the TNFR:Fc or IVIg treatment. (iii) As determined by real-time RT-PCR, both treatments reduced the expression of the hypertrophy-related genes, atrial natriuretic peptide and the ratio of beta/alpha-myosin heavy chains, and genes related to extracellular matrix remodeling (i.e., collagens I and III, matrix metalloproteinase [MMP]-2 and its tissue inhibitor TIMP-1) in the non-ischemic segment of LV and, in particular, in the RV. (iv) Treatment with IVIg, but not TNFR:Fc, reduced MMP-2 zymographic activity in the RV and the expression of genes for TNFalpha and monocyte chemoattractant protein-1. CONCLUSION: Therapy targeted directly against TNFalpha (i.e., TNFR:Fc) and a more general immunomodulatory approach (i.e., IVIg) in the acute phase of MI attenuates the cardiac remodeling process and expression of genes that are involved. These findings raise the possibility that initiation of immunomodulatory therapy post-MI could be beneficial in preventing the later development of heart failure.