David A. Bull

Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome

BACKGROUND Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function. METHODS We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days. RESULTS Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was -0.04±0.53 mg per deciliter (-3.5±46.9 μmol per liter) in the pharmacologic-therapy group, as compared with +0.23±0.70 mg per deciliter (20.3±61.9 μmol per liter) in the ultrafiltration group (P=0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg [12.1±11.3 lb] and 5.7±3.9 kg [12.6±8.5 lb], respectively; P=0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03). CONCLUSIONS In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00608491.).

Outcomes after esophagectomy: a ten-year prospective cohort

BACKGROUND The Department of Veterans Affairs National Surgical Quality Improvement Program is a unique resource to prospectively analyze surgical outcomes from a cross-section of surgical services nationally. We used this database to assess risk factors for morbidity and mortality after esophagectomy in Veterans Affairs Medical Centers from 1991 to 2001. METHODS A total of 1,777 patients underwent an esophagectomy at 109 Veterans Affairs hospitals with complete in-hospital and 30-day outcomes recorded. Bivariate and multivariable analyses were completed. RESULTS Thirty-day mortality was 9.8% (174/1,777) and the incidence of one or more of 20 predefined complications was 49.5% (880/1,777). The most frequent postoperative complications were pneumonia in 21% (380/1,777), respiratory failure in 16% (288/1,777), and ventilator support more than 48 hours in 22% (387/1,777). Preoperative predictors of mortality based on multivariable analysis included neoadjuvant therapy, blood urea nitrogen level of more than 40 mg/dL, alkaline phosphatase level of more than 125 U/L, diabetes mellitus, alcohol abuse, decreased functional status, ascites, and increasing age. Preoperative factors impacting morbidity were increasing age, dyspnea, diabetes mellitus, chronic obstructive pulmonary disease, alkaline phosphatase level of more than 125 U/L, lower serum albumin concentration, increased complexity score, and decreased functional status. Intraoperative risk factors for mortality included the need for transfusion; intraoperative risk factors for morbidity included the need for transfusion and longer operative time. CONCLUSIONS These data constitute the largest prospective outcomes cohort in the literature and document a near 50% morbidity rate and 10% mortality rate after esophagectomy. Data from this study can be used to better stratify patients before esophagectomy.

Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction The ROSE Acute Heart Failure Randomized Trial

IMPORTANCE Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. OBJECTIVE To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 μg/kg/min) or low-dose nesiritide (0.005 μg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m2), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. INTERVENTIONS Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119). MAIN OUTCOMES AND MEASURES Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point). RESULTS Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296 mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes. CONCLUSION AND RELEVANCE In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01132846.

Myocardial Stiffness in Patients With Heart Failure and a Preserved Ejection Fraction Contributions of Collagen and Titin

Background— The purpose of this study was to determine whether patients with heart failure and a preserved ejection fraction (HFpEF) have an increase in passive myocardial stiffness and the extent to which discovered changes depend on changes in extracellular matrix fibrillar collagen and cardiomyocyte titin. Methods and Results— Seventy patients undergoing coronary artery bypass grafting underwent an echocardiogram, plasma biomarker determination, and intraoperative left ventricular epicardial anterior wall biopsy. Patients were divided into 3 groups: referent control (n=17, no hypertension or diabetes mellitus), hypertension (HTN) without (–) HFpEF (n=31), and HTN with (+) HFpEF (n=22). One or more of the following studies were performed on the biopsies: passive stiffness measurements to determine total, collagen-dependent and titin-dependent stiffness (differential extraction assay), collagen assays (biochemistry or histology), or titin isoform and phosphorylation assays. In comparison with controls, patients with HTN(–)HFpEF had no change in left ventricular end-diastolic pressure, myocardial passive stiffness, collagen, or titin phosphorylation but had an increase in biomarkers of inflammation (C-reactive protein, soluble ST2, tissue inhibitor of metalloproteinase 1). In comparison with both control and HTN(–)HFpEF, patients with HTN(+)HFpEF had increased left ventricular end-diastolic pressure, left atrial volume, N-terminal propeptide of brain natriuretic peptide, total, collagen-dependent, and titin-dependent stiffness, insoluble collagen, increased titin phosphorylation on PEVK S11878(S26), reduced phosphorylation on N2B S4185(S469), and increased biomarkers of inflammation. Conclusions— Hypertension in the absence of HFpEF did not alter passive myocardial stiffness. Patients with HTN(+)HFpEF had a significant increase in passive myocardial stiffness; collagen-dependent and titin-dependent stiffness were increased. These data suggest that the development of HFpEF depends on changes in both collagen and titin homeostasis.

Water-soluble lipopolymer as an efficient carrier for gene delivery to myocardium

Water-soluble lipopolymer (WSLP), which consisted of polyethylenimine (PEI, 1800 Da) and cholesterol, was characterized as a gene carrier to smooth muscle cells and myocardium. Acid–base titration showed that WSLP had a proton-buffering effect. The size of WSLP/plasmid DNA (pDNA) complex was around 70 nm. WSLP/pDNA complex was transfected to A7R5 cells, a smooth muscle cell line. WSLP showed the highest transfection at a 40/1 N/P ratio. WSLP has higher transfection efficiency than PEI (1800 and 25 000 Da), SuperFect, and lipofectamine. In addition, WSLP has less cytotoxicity than PEI (25 000 Da), SuperFect, and lipofectamine. Since WSLP has cholesterol moiety, it may utilize cellular cholesterol uptake pathway, in which low-density lipoprotein (LDL) is involved. An inhibition study with free cholesterol or low-density lipoprotein (LDL) showed that transfection was inhibited by cholesterol or LDL, suggesting that WSLP/pDNA complex is transfected to the cells through the cholesterol uptake pathway. To evaluate the transfection efficiency to myocardium, WSLP/pDNA complex was injected into the rabbit myocardium. WSLP showed higher transfection than PEI and naked pDNA. WSLP expressed the transgene for more than 2 weeks. In conclusion, WSLP is an efficient carrier for local gene transfection to myocardium, and useful in in vivo gene therapy.

Contrast-induced nephrotoxicity: The effects of vasodilator therapy☆

The increasingly frequent use of contrast-enhanced imaging for diagnosis or intervention in patients with peripheral vascular disease has generated concern about the incidence and avoidance of contrast-induced nephrotoxicity (CIN). In this prospective study, we sought to identify those patients at greater risk of developing CIN and to evaluate the efficacy of vasodilator therapy with dopamine in limiting this complication. Baseline serum creatinine (Cr) concentrations were obtained on admission and daily for up to 72 hr after angiography in 222 patients undergoing 232 angiographic procedures. The preangiographic treatment was varied at 2-month intervals for 1 year. All patients received an intravenous infusion of 5% dextrose and 0.45% normal saline at a rate of 75 to 125 ml/hr. During the first interval patients received 12.5 g of 25% mannitol immediately prior to their contrast load, in addition to intravenous fluids. During the next 2-month period the patients were given renal dose dopamine intravenously (3 micrograms/kg/min) commencing the evening before angiography and continued to the next morning. During the latter half of the study the treatment regimens were modified so that the use of mannitol was restricted to patients with diabetes mellitus and dopamine to patients with serum creatinine concentrations of > or = 2 mg/dl. Postangiographic elevation in Cr occurred in 2, 10.4, and 62% of studies in patients with baseline creatinine levels of < or = 1.2 mg/dl, 1.3 to 1.9 mg/dl, and > or = 2.0 mg/dl, respectively. None of the patients receiving dopamine experienced an elevation in creatinine. There was no statistical correlation between age, diabetes, or medication with calcium channel blockers and CIN.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoxia-inducible VEGF gene delivery to ischemic myocardium using water-soluble lipopolymer

Therapeutic angiogenesis with gene encoding vascular endothelial growth factor (VEGF) is a new potential treatment in cardiovascular disease. However, unregulated VEGF-mediated angiogenesis has the potential to promote tumor growth, accelerate diabetic proliferative retinopathy, and promote rupture of atherosclerotic plaque. To be safe and effective, gene therapy with VEGF must be regulated. To limit the risk of pathological angiogenesis, we developed a hypoxia-inducible VEGF gene therapy system using the erythropoietin (Epo) enhancer and water-soluble lipopolymer (WSLP). pEpo-SV-VEGF or pSV-VEGF-Epo was constructed by insertion of the Epo enhancer upstream of the Simian Virus 40 (SV40) promoter or downstream of the poly(A) signal of pSV-VEGF. In vitro transfection showed that pEpo-SV-VEGF, not pSV-VEGF-Epo, induced the VEGF expression in hypoxic cells. In addition, the VEGF protein, which was produced from the Epo-SV-VEGF-transfected and hypoxia-incubated cells, was able to enhance the proliferation of the endothelial cells. Injection of the pEpo-SV-VEGF/WSLP complex showed that the expression of VEGF was induced in ischemic myocardium, compared to normal myo-cardium. Therefore, with the localized induction of VEGF and the low cytotoxicity of WSLP, the pEpo-SV-VEGF/WSLP system may be helpful to eventually treat ischemic heart disease.

Coronary artery bypass grafting with cardiopulmonary bypass versus off-pump cardiopulmonary bypass grafting: does eliminating the pump reduce morbidity and cost?

BACKGROUND Cardiopulmonary bypass (CPB) may contribute to the complications and cost of coronary artery bypass grafting (CABG). Off-pump CABG (OPCAB) allows coronary revascularization without CPB. We hypothesized that OPCAB provides satisfactory graft patency while reducing complications and cost compared with CABG with CPB. METHODS We prospectively followed 80 patients undergoing CABG: 40 patients undergoing OPCAB and 40 patients undergoing CABG with CPB. OPCAB patients underwent angiography within 48 hours of surgery to determine early graft patency. Incidence of complications, length of stay, and costs were recorded for each patient. The influence of the number of vessels bypassed was analyzed. RESULTS OPCAB patients (n = 40) underwent grafting of 2.7 +/- 0.7 vessels per patient compared with 3.6 +/- 0.8 vessels per patient in the CABG with CPB group (n = 40) (p < 0.0001). Angiography demonstrated 105 of 108 (97%) of grafts were patent in the OPCAB group. Incidence of complications, length of stay, and costs did not differ between the OPCAB and CABG with CPB groups. Number of vessels grafted showed a positive correlation to total costs in both groups. CONCLUSIONS While OPCAB provided satisfactory early graft patency, there was no significant difference between OPCAB and CABG with CPB with regard to cost, length of stay, or incidence of complications. In this study, eliminating CPB did not reduce morbidity or cost after CABG.

VEGF siRNA delivery system using arginine-grafted bioreducible poly(disulfide amine).

Small interfering RNAs (siRNAs) are able to silence their target genes when they are successfully delivered intact into the cytoplasm. Delivery systems that enhance siRNA localization to the cytoplasm can facilitate gene silencing by siRNA therapeutics. We describe an arginine-conjugated poly(cystaminebisacrylamide-diaminohexane) (poly(CBA-DAH-R)), a bioreducible cationic polymer, as an siRNA carrier for therapeutic gene silencing for cancer. After intracellular uptake of the siRNA/poly(CBA-DAH-R) polyplexes, the reductive environment of the cytoplasm cleaves the disulfide linkages in the polymeric backbone, resulting in decomplexing of the siRNA/poly(CBA-DAH-R) polyplexes and release of siRNA molecules throughout the cytoplasm. The siRNA/poly(CBA-DAH-R) polyplexes, which demonstrate increased membrane permeability with arginine modification, have a similar level of cellular uptake as siRNA/bPEI polyplexes. The VEGF siRNA/poly(CBA-DAH-R) polyplexes, however, inhibit VEGF expression to a greater degree than VEGF siRNA/bPEI in various human cancer cell lines. The improved RNAi activity demonstrated by the VEGF siRNA/poly(CBA-DAH-R) polyplexes is due to enhanced intracellular delivery and effective localization to the cytoplasm of the VEGF siRNAs. These results demonstrate that the VEGF siRNA/poly(CBA-DAH-R) polyplex delivery system may useful for siRNA-based approaches for cancer therapy.

A family of bioreducible poly(disulfide amine)s for gene delivery

A family of bioreducible poly(disulfide amine)s, which differ in the length of polymethylene spacer [-(CH(2))(n)-] in the main chain and the side chain, has been synthesized. These bioreducible poly(disulfide amine)s exhibit local environment specific degradability and are associated with lower cytotoxicity than branched poly(ethylenimine) (bPEI, 25 kDa). These cationic polymers also show higher buffering capacity and protonation degree than bPEI, facilitating the endosomal escape of carried genetic materials. The transfection efficiency of these agents is oligomethylene length dependent. Poly(cystaminebisacrylamide-spermine) [poly(CBA-SP)], poly(cystaminebisacrylamide-bis(3-aminopropyl)-1,3-propanediamine) [poly(CBA-APPD)], and poly(cyxtaminebisacrylamide-bis(3-aminopropyl)-ethylenediamine) [ploy(CBA-APED)] with longer propylene [-(CH(2))(3)-] side spacer, demonstrate higher transfection efficacy than the counterpart poly(cystaminebisacrylamide-bis(2-aminoethyl)-1,3-propanediamine) [poly(CBA-AEPD)] and poly(cystaminebisacrylamide-triethylenetetramine) [poly(CBA-TETA)], which have shorter ethylene [-(CH(2))(2)-] side spacer. The poly(CBA-SP), poly(CBA-APPD), poly(CBA-APED) with the main chain spacer of -(CH(2))(4)-, -(CH(2))(3)-, -(CH(2))(2)- demonstrate similar transfection efficiency, indicating the length of polymer main chain spacer has less influence on transfection efficiency. However, with the same short ethylene [-(CH(2))(2)-] side spacer, poly(CBA-AEPD), with the longer main chain oligomethylene units [-(CH(2))(3)-], showed relatively higher transfection efficiency than poly(CBA-TETA), having shorter main chain oligomethylene units [-(CH(2))(2)-]. Of these polymeric carriers, poly(CBA-SP) demonstrated the highest transfection in the C2C12 cell line, while poly(CBA-APED) showed the highest transfection in the HeLa cell line. All of these agents showed greater transfection activity than commercialized bPEI 25 kDa. The poly(disulfide amine)s are promising safe and efficient non-viral vectors for gene delivery.