Dipeptidyl Peptidase-4 Inhibitor Decreases Allograft Vasculopathy Via Regulating the Functions of Endothelial Progenitor Cells in Normoglycemic Rats.

PURPOSE: Chronic rejection induces the occurrence of orthotopic allograft transplantation (OAT) vasculopathy, which results in failure of the donor organ. Numerous studies have demonstrated that in addition to regulating blood sugar homeostasis, dipeptidyl peptidase-4 (DPP-4) inhibitors can also provide efficacious therapeutic and protective effects against cardiovascular diseases. However, their effects on OAT-induced vasculopathy remain unknown. Thus, the aim of this study was to investigate the direct effects of sitagliptin on OAT vasculopathy in vivo and in vitro. METHODS: The PVG/Seac rat thoracic aorta graft to ACI/NKyo rat abdominal aorta model was used to explore the effects of sitagliptin on vasculopathy. Human endothelial progenitor cells (EPCs) were used to investigate the possible underlying mechanisms. RESULTS: We demonstrated that sitagliptin decreases vasculopathy in OAT ACI/NKyo rats. Treatment with sitagliptin decreased BNP and HMGB1 levels, increased GLP-1 activity and stromal cell-derived factor 1α (SDF-1α) expression, elevated the number of circulating EPCs, and improved the differentiation possibility of mononuclear cells to EPCs ex vivo. However, in vitro studies showed that recombinant B-type natriuretic peptide (BNP) and high mobility group box 1 (HMGB1) impaired EPC function, whereas these phenomena were reversed by glucagon-like peptide 1 (GLP-1) receptor agonist treatment. CONCLUSIONS: We suggest that the mechanisms underlying sitagliptin-mediated inhibition of OAT vasculopathy probably occur through a direct increase in GLP-1 activity. In addition to the GLP-1-dependent pathway, sitagliptin may regulate SDF-1α levels and EPC function to reduce OAT-induced vascular injury. This study may provide new prevention and treatment strategies for DPP-4 inhibitors in chronic rejection-induced vasculopathy.

Hypervolemia does not cause degradation of the endothelial glycocalyx layer during open hysterectomy performed under sevoflurane or propofol anesthesia.

BACKGROUND: Fluid-induced hypervolemia may stimulate the release of natriuretic peptides and cause degradation (shedding) of the endothelial glycocalyx layer. Sevoflurane is believed to protect the glycocalyx, but the importance of using sevoflurane to prevent shedding during routine surgery is unclear. METHODS: The plasma concentrations of brain natriuretic peptide and two biomarkers of glycocalyx shedding, syndecan-1, and heparan sulfate, were measured in 26 patients randomized to receive general anesthesia with sevoflurane or propofol during open abdominal hysterectomy. The fluid therapy consisted of 25 mL/kg (approximately 2 L) of Ringer´s lactate over 30 minutes. Blood hemoglobin and plasma albumin were used to indicate plasma volume expansion and capillary leakage. RESULTS: The plasma concentrations of brain natriuretic peptide and shedding products showed low levels throughout the surgery (median brain natriuretic peptide, 21 ng/L; syndecan-1, 12.9 ng/mL; and heparan sulfate, 6.5 µg/mL), but the heparan sulfate concentration increased 2 hours post-operatively (to 17.3 µg/mL, P < .005). No differences were noted between the propofol and sevoflurane groups in any of the measured parameters. Albumin was apparently recruited to the bloodstream during the first 20 minutes, when the intravascular retention of infused fluid was almost 100%. The urine flow was <1 mL/min, despite the vigorous volume loading. CONCLUSIONS: No relevant elevations of brain natriuretic peptide or degradation products of the glycocalyx layer were observed when hypervolemia was induced during open abdominal hysterectomy performed with sevoflurane or propofol anesthesia. Plasma volume expansion from Ringer´s lactate was pronounced.

Elevated BNP caused by recombinant human interleukin-11 treatment in patients with chemotherapy-induced thrombocytopenia.

Thrombocytopenia is a condition characterized by abnormally low levels of thrombocytes and often induced by chemotherapy. Recombinant human interleukin-11 (rhIL-11) is a cytokine that can stimulate thrombopoiesis and is commonly used to treat thrombocytopenia. We observed the side effects of rhIL-11 in 24 leukemia patients with chemotherapy-induced thrombocytopenia. To determine the cardiovascular effects of rhIL-11, we detected changes in the patients' serum brain natriuretic peptide (BNP), blood pressure fluctuations, weight change, and whether edema or heart failure occurred in leukemia patients after chemotherapy. The results showed that BNP was significantly elevated after using rhIL-11 (P < 0. 05) but regressed after 2-4 days. Furthermore, nine patients had edema and experienced weight gain, and four experienced acute left heart failure. In addition, the average blood pressure was 119/75 mmHg (range 139/86 mmHg to 99/64 mmHg) before rhIL-11 administration and 127/79 mmHg (range 146/89 mmHg to 108/69 mmHg) after rhIL-11 use. In conclusion, although rhIL-11 is useful for treating chemotherapy-induced thrombocytopenia, it is important to monitor the patients' clinical status and re-examine BNP levels frequently during the use of rhIL-11. Furthermore, senile patients should be given special attention. However, the appropriate timing to begin and discontinue rhIL-11 treatment needs further investigation.

Novel endotypes in heart failure: effects on guideline-directed medical therapy.

Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. Methods and results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort. Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.

Macitentan in pulmonary hypertension due to left ventricular dysfunction.

The MELODY-1 study evaluated macitentan for pulmonary hypertension because of left heart disease (PH-LHD) in patients with combined post- and pre-capillary PH.63 patients with PH-LHD and diastolic pressure gradient ≥7 mmHg and pulmonary vascular resistance (PVR) >3WU were randomised to macitentan 10 mg (n=31) or placebo (n=32) for 12 weeks. The main end-point assessed a composite of significant fluid retention (weight gain ≥5% or ≥5 kg because of fluid overload or parenteral diuretic administration) or worsening in New York Heart Association functional class from baseline to end of treatment. Exploratory end-points included changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) and haemodynamics at week 12.Seven macitentan-treated and four placebo-treated patients experienced significant fluid retention/worsening functional class; treatment difference, 10.08% (95% CI -15.07-33.26; p=0.34). The difference, driven by the fluid retention component, was apparent within the first month. At week 12, versus placebo, the macitentan group showed no change in PVR, mean right atrial pressure or pulmonary arterial wedge pressure; a non-significant increase in cardiac index (treatment effect 0.4 (95% CI 0.1-0.7) L·min-1·m-2) and decrease in NT-proBNP (0.77 (0.55-1.08)) was observed. Adverse events and serious adverse events were numerically more frequent with macitentan versus placebo.Macitentan-treated patients were quantitatively more likely to experience significant fluid retention versus placebo. Macitentan resulted in no significant changes in any exploratory end-points.

Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial.

OBJECTIVE: The objective is to assess the safety, tolerability, and efficacy of sacubitril/valsartan compared with enalapril in patients with heart failure (HF) with a reduced ejection fraction (EF) stabilized during hospitalization for acute decompensated HF. BACKGROUND: Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitor, improves survival among ambulatory HF patients with a reduced EF. However, there is very limited experience with the in-hospital initiation of sacubitril/valsartan in patients who have been stabilized following hospitalization for acute decompensated HF. METHODS: PIONEER-HF is a 12-week, prospective, multicenter, double-blind, randomized controlled trial enrolling a planned 882 patients at more than 100 participating sites in the United States. Medically stable patients >18 years of age with an EF <40% and an amino terminal-pro b-type natriuretic peptide >1600 pg/mL or b-type natriuretic peptide >400 pg/mL are eligible for participation no earlier than 24 hours and up to 10 days from initial presentation while still hospitalized. Patients are randomly assigned 1:1 to in-hospital initiation of sacubitril/valsartan titrated to 97/103 mg by mouth twice daily versus enalapril titrated to 10 mg by mouth twice daily for 8 weeks. All patients receive open-label treatment with sacubitril/valsartan for the remaining 4 weeks of the study. The primary efficacy end point is the time-averaged proportional change in amino terminal-pro b-type natriuretic peptide from baseline through weeks 4 and 8. Secondary and exploratory end points include serum and urinary biomarkers as well as clinical outcomes. Safety end points include the incidence of angioedema, hypotension, renal insufficiency, and hyperkalemia. CONCLUSION: The PIONEER-HF trial will inform clinical practice by providing evidence on the safety, tolerability, and efficacy of in-hospital initiation of sacubitril/valsartan among patients who have been stabilized following an admission for acute decompensated HF with a reduced EF.

Randomized Trial of Effect of Urate-Lowering Agent Febuxostat in Chronic Heart Failure Patients with Hyperuricemia (LEAF-CHF).

Hyperuricemia is an independent predictor of mortality in patients with chronic heart failure. The aim of the study is to determine whether a urate-lowering agent febuxostat, an inhibitor of xanthine oxidase, may improve the clinical outcomes in chronic heart failure patients with hyperuricemia when compared to conventional treatment. This multicenter, prospective, randomized, open-label, blinded endpoint study with a follow-up period of 24 weeks will enroll 200 Japanese chronic heart failure patients with hyperuricemia. The eligibility criteria include a diagnosis of chronic heart failure (New York Heart Association functional class II-III with a history of hospitalization due to worsening of heart failure within the last 2 years), reduced left ventricular systolic function (left ventricular ejection fraction < 40%) and increased plasma natriuretic peptide [plasma B-type natriuretic peptide (BNP) ≥ 100 pg/mL or N-terminal pro BNP (NT-proBNP) ≥ 400 pg/mL], and hyperuricemia (serum uric acid >7.0 mg/dL and ≤ 10 mg/dL) at the screening visit. The primary outcome is the difference in the plasma BNP levels between the baseline and 24 weeks of treatment. The plasma BNP levels are measured in the central laboratory in a blinded manner. This study investigates the efficacy and safety of febuxostat in chronic heart failure patients with hyperuricemia.

Intracoronary delivery of recombinant TIMP-3 after myocardial infarction: effects on myocardial remodeling and function.

Ischemia-reperfusion (IR) and myocardial infarction (MI) cause adverse left ventricular (LV) remodeling and heart failure and are facilitated by an imbalance in matrix metalloproteinase (MMP) activation and the endogenous tissue inhibitors of metalloproteinase (TIMPs). We have identified that myocardial injections of recombinant TIMP-3 (rTIMP-3; human full length) can interrupt post-MI remodeling. However, whether and to what degree intracoronary delivery of rTIMP-3 post-IR is feasible and effective remained to be established. Pigs (25 kg) underwent coronary catheterization and balloon occlusion of the left anterior descending coronary artery (LAD) for 90 min whereby at the final 4 min, rTIMP-3 (30 mg, n = 9) or saline was infused in the distal LAD. LV echocardiography was performed at 3-28 days post-IR, and LV ejection fraction (EF) and LV end-diastolic volume were measured. LV EF fell and LV end-diastolic volume increased from baseline (pre-IR) values (66 ± 1% and 40 ± 1 ml, respectively, means ± standard deviation) in both groups; however, the extent of LV dilation was reduced in the rTIMP-3 group by 40% at 28 days post-IR (P < 0.05) and the fall in LV EF was attenuated. Despite equivalent plasma troponin levels (14 ± 3 ng/ml), computed MI size at 28 days was reduced by over 45% in the rTIMP-3 group (P < 0.05), indicating that rTIMP-3 treatment abrogated MI expansion post-IR. Plasma NH2-terminal pro-brain natriuretic peptide levels, an index of heart failure progression, were reduced by 25% in the rTIMP-3 group compared with MI saline values (P < 0.05). Although the imbalance between MMPs and TIMPs has been recognized as a contributory factor for post-MI remodeling, therapeutic strategies targeting this imbalance have not been forthcoming. This study is the first to demonstrate that a relevant delivery approach (intracoronary) using rTIMP can alter the course of post-MI remodeling.NEW & NOTEWORTHY Myocardial ischemia and reperfusion injury remain significant causes of morbidity and mortality whereby alterations in the balance between matrix metalloproteinase and tissue inhibitor of metalloproteinase have been identified as contributory biological mechanisms. This novel translational study advances the concept of targeted delivery of recombinant proteins to modify adverse myocardial remodeling in ischemia-reperfusion injury.

Resolution of Cheyne-Stokes Respiration after Treatment of Heart Failure with Sacubitril/Valsartan: A First Case Report.

Sleep-disordered breathing (SDB) is highly prevalent in patients with heart failure (HF), and is known to be associated with a worse prognosis. The severity of central sleep apnea is thought to mirror cardiac dysfunction. The novel angiotensin receptor-neprilysin inhibitor (ARNi) sacubitril has been shown to improve HF, but a relationship between treatment with ARNi and the severity of SDB has not yet been investigated. We report the case of a 71-year-old male with HF and SDB. Treatment with sacubitril/valsartan was associated with improved cardiac function, as shown by a reduction in the level of N-terminal prohormone of brain natriuretic peptide from 3,249 to 1,720 pg/mL, and an improvement in left-ventricular ejection fraction from 30 to 35%. This was accompanied by a marked reduction in the apnea-hypopnea index (from 41 to 19/h). To the best of our knowledge, this is the first case to document parallel improvements in HF and SDB after the initiation of ARNi treatment.

Carvedilol and Cardiac Biomarkers in Dialysis Patients: Secondary Analysis of a Randomized Controlled Trial.

BACKGROUND/AIMS: Cardiac biomarkers are associated with cardiac abnormalities and adverse outcomes in dialysis patients. Our aim was to report the effect of the beta-blocker carvedilol on cardiac biomarkers in adult dialysis patients. METHODS: The Beta-Blocker to Lower Cardiovascular Dialysis Events Feasibility Study was a randomized controlled trial comparing carvedilol to placebo. Serum and plasma were collected before the run-in, then 6 and 12 months post-randomization to measure B-type Natriuretic Peptide (BNP), N-terminal BNP (NT-ProBNP), high-sensitivity cardiac troponins I (hs-TnI) and T (hs-TnT), and galectin-3. Left ventricular global longitudinal strain (GLS) was measured by echocardiography at baseline. RESULTS: Seventy-two participants were recruited of whom 49 completed the run-in and were randomized to carvedilol (n=26) or placebo (n=23). Baseline echocardiography demonstrated median (inter-quartile range) GLS of -14.27% (-16.63 to -11.93). NTproBNP and hs-TnT correlated with GLS (Spearman's rho=0.34 [p=0.018] and rho=0.28 [p=0.049], respectively). Median change scores from baseline to 12 months did not differ significantly between participants with complete biomarker data randomized to carvedilol (n=15) or placebo (n=16) for any biomarkers. CONCLUSIONS: NT-proBNP and hs-TnT were associated with GLS. However, changes in levels of the biomarkers from baseline to 12 months were not different between groups randomized to carvedilol and placebo.

Combination of angiotensin II and l-NG-nitroarginine methyl ester exacerbates mitochondrial dysfunction and oxidative stress to cause heart failure.

Mitochondrial dysfunction has been implicated as a cause of energy deprivation in heart failure (HF). Herein, we tested individual and combined effects of two pathogenic factors of nonischemic HF, inhibition of nitric oxide synthesis [with l-N(G)-nitroarginine methyl ester (l-NAME)] and hypertension [with angiotensin II (AngII)], on myocardial mitochondrial function, oxidative stress, and metabolic gene expression. l-NAME and AngII were administered individually and in combination to mice for 5 wk. Although all treatments increased blood pressure and reduced cardiac contractile function, the l-NAME + AngII group was associated with the most severe HF, as characterized by edema, hypertrophy, oxidative stress, increased expression of Nppa and Nppb, and decreased expression of Atp2a2 and Camk2b. l-NAME + AngII-treated mice exhibited robust deterioration of cardiac mitochondrial function, as observed by reduced respiratory control ratios in subsarcolemmal mitochondria and reduced state 3 levels in interfibrillar mitochondria for complex I but not for complex II substrates. Cardiac myofibrils showed reduced ADP-supported and oligomycin-inhibited oxygen consumption. Mitochondrial functional impairment was accompanied by reduced mitochondrial DNA content and activities of pyruvate dehydrogenase and complex I but increased H2O2 production and tissue protein carbonyls in hearts from AngII and l-NAME + AngII groups. Microarray analyses revealed the majority of the gene changes attributed to the l-NAME + AngII group. Pathway analyses indicated significant changes in metabolic pathways, such as oxidative phosphorylation, mitochondrial function, cardiac hypertrophy, and fatty acid metabolism in l-NAME + AngII hearts. We conclude that l-NAME + AngII is associated with impaired mitochondrial respiratory function and increased oxidative stress compared with either l-NAME or AngII alone, resulting in nonischemic HF.

Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension.

BACKGROUND: Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH. METHODS: In this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints. RESULTS: At 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05). CONCLUSIONS: Up-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).

Sevoflurane Versus Total Intravenous Anesthesia for Isolated Coronary Artery Bypass Surgery With Cardiopulmonary Bypass: A Randomized Trial.

OBJECTIVE: Several studies have suggested that the cardioprotective effects of halogenated anesthetics in cardiac surgery result in reduced cardiac biomarker release compared with total intravenous anesthesia (TIVA). These findings came from relatively small randomized clinical trials and meta-analyses. The authors of this study hypothesized that the beneficial effects of volatile anesthetics translate into a reduced length of hospital stay after coronary artery bypass grafting surgery (CABG) with cardiopulmonary bypass. DESIGN: A randomized controlled trial. SETTING: Two university hospitals. PARTICIPANTS: Adult patients undergoing elective CABG surgery with cardiopulmonary bypass. INTERVENTIONS: Patients were assigned randomly to 2 following groups: propofol-based TIVA group (n = 431) and sevoflurane group (n = 437). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was hospital length of stay, and the secondary endpoint included postoperative troponin T and N-terminal pro-brain natriuretic peptide release and mortality. In the sevoflurane group, a reduced length of hospital stay was observed compared with the propofol-based TIVA group (10 [9-11] days v 14 [10-16], p<0.001) as were reductions in cardiac troponin T release (0.18 ng/mL v 0.57 ng/mL at 24 hours, p<0.001), in N-terminal pro-brain natriuretic peptide release (633 pg/mL v 878 pg/mL at 24 hours, p<0.001; 482 pg/mL v 1,036 pg/mL at 48 hours, p<0.001), and in mortality at 1-year follow up (17.8% v 24.8%, p = 0.03). CONCLUSIONS: Anesthesia with sevoflurane reduced cardiac biomarker release and length of hospital stay after CABG with cardiopulmonary bypass surgery compared with propofol-based TIVA with a possible reduction in 1-year mortality.

Calcium channel blockers improve exercise capacity and reduce N-terminal Pro-B-type natriuretic peptide levels compared with beta-blockers in patients with permanent atrial fibrillation.

AIMS: Rate control of atrial fibrillation (AF) has become a main treatment modality, but we need more knowledge regarding the different drugs used for this purpose. In this study, we aimed to compare the effect of four common rate-reducing drugs on exercise capacity and levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with permanent AF. METHODS AND RESULTS: We included 60 patients (mean age 71 ± 9 years, 18 women) with permanent AF and normal left ventricular function in a randomized, cross-over, investigator-blind study. Diltiazem 360 mg, verapamil 240 mg, metoprolol 100 mg, and carvedilol 25 mg were administered o.d. for 3 weeks. At baseline and on the last day of each treatment period, the patients underwent a maximal cardiopulmonary exercise test and blood samples were obtained at rest and at peak exercise. The exercise capacity (peak VO2) was significantly lower during treatment with metoprolol and carvedilol compared with baseline (no treatment) or treatment with diltiazem and verapamil (P < 0.001 for all). Compared with baseline, treatment with diltiazem and verapamil significantly reduced the NT-proBNP levels both at rest and at peak exercise, whereas treatment with metoprolol and carvedilol increased the levels (P < 0.05 for all). CONCLUSION: Rate-reducing treatment with diltiazem or verapamil preserved exercise capacity and reduced levels of NT-proBNP compared with baseline, whereas treatment with metoprolol or carvedilol reduced the exercise capacity and increased levels of NT-proBNP.

Upgraded heart failure therapy leads to an improved outcome of dilated cardiomyopathy in infants and toddlers.

OBJECTIVE: Dilated cardiomyopathy is a leading cause of cardiac death in children. Approximately 30% of children die or need cardiac transplantation in the first year after establishing the diagnosis. New strategies are needed to improve the outcome in this high-risk patient population. METHOD AND RESULTS: We present our experience in 38 patients below the age of three years, who were diagnosed with dilated cardiomyopathy and who were treated at our institution between 2006 and 2012. The treatment strategy involved institution of ß-blockers and angiotensin-converting enzyme inhibitors as soon as feasible. In selected cases, pulmonary artery banding or intracoronary autologous bone marrow-derived cell therapy was performed. The median age at presentation was six months (range 1-26 months). The median follow-up age was 16 months (range 2-80 months). Kaplan-Meier analysis of survival after dilated cardiomyopathy diagnosis revealed a one-year survival of 97% and a five-year survival of 86%. The rate of freedom from death or heart transplantation was 82% at one year and 69% at five years. Surviving patients who were free of transplantation, at the follow-up at 25 months (3-80 months), showed a significant improvement in left ventricular ejection fraction (from 19±11 to 46±16%) and left ventricular end-diastolic diameter (z-score from 4.6±2.4 to 1.4±1.6). In addition, the levels of B-type natriuretic peptide improved significantly (from 3330±3840 to 171±825 pg/ml). CONCLUSION: Our data suggest that the clinical approach described here may result in a markedly improved medium-term outcome in young children with dilated cardiomyopathy. Further studies are required to evaluate whether these approaches reduce end-points such as transplantation or death.

[Effects of Qili Qiangxin capsules on NT-proBNP level and cardiac function in silicosis patients].

OBJECTIVE: To investigate the effects of Qili Qiangxin capsules on the amino-terminal pro-brain natriuretic peptide (NT-proBNP) level and cardiac function in patients with silicosis. METHODS: Hospitalized silicosis patients with heart failure were divided into treatment group (41 cases) and control group (30 cases) according to their own will. Both groups received comprehensive symptomatic treatment; in addition, the treatment group received Qili Qiangxin capsules. The treatment lasted 6 months. The observed items included NT-proBNP level, 6-minute walk test, ultrasonic cardiogram, and NYHA classification before and after treatment. RESULTS: According to NYHA classification, the response rate was 29.27%in the treatment group and 10.00%in the control group; there was a significant difference between the two groups (P < 0.05). The average walk distance in the treatment group was increased from 150.96±73.12 m before treatment to 169.32±77.04 m after treatment, and the improvement was statistically significant (P < 0.05). The average NT-proBNP level in the treatment group was reduced from 1154.44 ± 480.79 ng/L before treatment to 494.49 ± 342.61 ng/L after treatment, and the reduction was statistically significant (P < 0.01). Left ventricular ejection fraction was significantly improved in the treatment group (P < 0.05). CONCLUSION: Qili Qiangxin capsules in addition to comprehensive symptomatic treatment can significantly reduce NT-proBNP level and improve cardiac function in silicosis patients, and thereby improve patients' quality of life.

Troponin I release after intravenous treatment with high furosemide doses plus hypertonic saline solution in decompensated heart failure trial (Tra-HSS-Fur).

BACKGROUND: High values of cardiac troponin in acute decompensated congestive heart failure (ADHF) identify patients at higher risk and worsened prognosis. A cardiac troponin increase during therapy indicates the need for more appropriate intervention, aimed at compensating cardiac disease and effectively minimizing myocardial wall stress and subsequent cytolysis. This study evaluated the effects of an intravenous high dose of furosemide with (group A) or without small volume hypertonic saline solution (HSS) (group B) on myocardial cytolysis in patients with ADHF. METHODS: A total of 248 consecutive patients with ADHF (148 men, mean age 74.9 ± 10.9 years) were randomly assigned to group A or B. Plasma levels of cardiac troponin-I, brain natriuretic peptide, glomerular filtration rate by Modification of Diet in Renal Disease formula, bioelectrical impedance analysis measurements, and delta pressure/delta time (dP/dt) rate were observed on admission and discharge for all patients. RESULTS: We observed a significant reduction of cardiac troponin in both groups and a significant improvement in renal function, hydration state, pulmonary capillary wedge pressure (P < .0001), end diastolic volume (P < .01), ejection fraction (P < .01), and dP/dt (P < .004) in group A. We also observed a significant reduction in body weight (64.4 vs 75.8 kg) (P < .001), cardiac troponin I (0.02 vs 0.31 ng/mL) (P < .0001) and brain natriuretic peptide (542 vs 1,284 pg/mL) (P < .0001), and hospitalization time (6.25 vs 10.2 days) (P < .0001) in the HSS group. CONCLUSIONS: These data demonstrate that intravenous high doses of furosemide do not increase myocardial injury and, in addition, when associated to HSS, significantly reduce cardiac troponin I release. This behavior is mirrored by the achievement of improved hemodynamic compensation at echocardiography and body hydration normalization.

Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease.

BACKGROUND: Left atrial enlargement, a sensitive integrator of left ventricular diastolic function, is associated with increased cardiovascular morbidity and mortality. Vitamin D is linked to lower cardiovascular morbidity, possibly modifying cardiac structure and function; however, firm evidence is lacking. We assessed the effect of an activated vitamin D analog on left atrial volume index (LAVi) in a post hoc analysis of the PRIMO trial (clinicaltrials.gov: NCT00497146). METHODS AND RESULTS: One hundred ninety-six patients with chronic kidney disease (estimated glomerular filtration rate 15-60 mL/min per 1.73 m(2)), mild to moderate left ventricular hypertrophy, and preserved ejection fraction were randomly assigned to 2 µg of oral paricalcitol or matching placebo for 48 weeks. Two-dimensional echocardiography was obtained at baseline and at 24 and 48 weeks after initiation of therapy. Over the study period, there was a significant decrease in LAVi (-2.79 mL/m(2), 95% CI -4.00 to -1.59 mL/m(2)) in the paricalcitol group compared with the placebo group (-0.70 mL/m(2) [95% CI -1.93 to 0.53 mL/m(2)], P = .002). Paricalcitol also attenuated the rise in levels of brain natriuretic peptide (10.8% in paricalcitol vs 21.3% in placebo, P = .02). For the entire population, the change in brain natriuretic peptide correlated with change in LAVi (r = 0.17, P = .03). CONCLUSIONS: Forty-eight weeks of therapy with an active vitamin D analog reduces LAVi and attenuates the rise of BNP. In a population where only few therapies alter cardiovascular related morbidity and mortality, these post hoc results warrant further confirmation.

Quality of life and chronic heart failure therapy guided by natriuretic peptides: results from the ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) study.

BACKGROUND: Heart failure (HF) treatment guided by amino-terminal pro-B type natriuretic peptide (NT-proBNP) may reduce cardiovascular event rates compared to standard-of-care (SOC) management. Comprehensive understanding regarding effect of NT-proBNP guided care on patient-reported quality of life (QOL) remains unknown. METHODS: One hundred fifty-one subjects with HF due to left ventricular systolic dysfunction were randomized to either SOC HF management or care with a goal to reduce NT-proBNP values ≤1000 pg/mL. Effects of HF on QOL were assessed using the Minnesota Living with HF Questionnaire (MLHFQ) quarterly, with change (Δ) in score assessed across study procedures and as a function of outcome. RESULTS: Overall, baseline MLHFQ score was 30. Across study visits, QOL improved in both arms, but was more improved and sustained in the NT-proBNP arm (repeated measures P = .01); NT-proBNP patients showing greater reduction in MLHFQ score (-10.0 vs -5.0; P = .05), particularly in the physical scale of the questionnaire. Baseline MLHFQ scores did not correlate with NT-proBNP; in contrast, ∆MLHFQ scores modestly correlated with ∆NT-proBNP values (ρ = .234; P = .006) as did relative ∆ in MLHFQ score and NT-proBNP (ρ = .253; P = .003). Considered in tertiles, less improvement in MLHFQ scores was associated with a higher rate of HF hospitalization, worsening HF, and cardiovascular death (P = .001). CONCLUSIONS: We describe novel associations between NT-proBNP concentrations and QOL scores among patients treated with biomarker guided care. Compared to SOC HF management, NT-proBNP guided care was associated with greater and more sustained improvement in QOL (Clinical Trial Registration: www.clinicaltrials.govNCT00351390).