Progress toward a vaccine for extraintestinal pathogenic E. coli (ExPEC) II: efficacy of a toxin-autotransporter dual antigen approach.

Extraintestinal pathogenic Escherichia coli (ExPEC) is a leading cause of worldwide morbidity and mortality, the top cause of antimicrobial-resistant (AMR) infections, and the most frequent cause of life-threatening sepsis and urinary tract infections (UTI) in adults. The development of an effective and universal vaccine is complicated by this pathogen's pan-genome, its ability to mix and match virulence factors and AMR genes via horizontal gene transfer, an inability to decipher commensal from pathogens, and its intimate association and co-evolution with mammals. Using a pan virulome analysis of >20,000 sequenced E. coli strains, we identified the secreted cytolysin α-hemolysin (HlyA) as a high priority target for vaccine exploration studies. We demonstrate that a catalytically inactive pure form of HlyA, expressed in an autologous host using its own secretion system, is highly immunogenic in a murine host, protects against several forms of ExPEC infection (including lethal bacteremia), and significantly lowers bacterial burdens in multiple organ systems. Interestingly, the combination of a previously reported autotransporter (SinH) with HlyA was notably effective, inducing near complete protection against lethal challenge, including commonly used infection strains ST73 (CFT073) and ST95 (UTI89), as well as a mixture of 10 of the most highly virulent sequence types and strains from our clinical collection. Both HlyA and HlyA-SinH combinations also afforded some protection against UTI89 colonization in a murine UTI model. These findings suggest recombinant, inactive hemolysin and/or its combination with SinH warrant investigation in the development of an E. coli vaccine against invasive disease.

Broad protective vaccination against systemic Escherichia coli with autotransporter antigens.

Extraintestinal pathogenic Escherichia coli (ExPEC) is the leading cause of adult life-threatening sepsis and urinary tract infections (UTI). The emergence and spread of multidrug-resistant (MDR) ExPEC strains result in a considerable amount of treatment failure and hospitalization costs, and contribute to the spread of drug resistance amongst the human microbiome. Thus, an effective vaccine against ExPEC would reduce morbidity and mortality and possibly decrease carriage in healthy or diseased populations. A comparative genomic analysis demonstrated a gene encoding an invasin-like protein, termed sinH, annotated as an autotransporter protein, shows high prevalence in various invasive ExPEC phylogroups, especially those associated with systemic bacteremia and UTI. Here, we evaluated the protective efficacy and immunogenicity of a recombinant SinH-based vaccine consisting of either domain-3 or domains-1,2, and 3 of the putative extracellular region of surface-localized SinH. Immunization of a murine host with SinH-based antigens elicited significant protection against various strains of the pandemic ExPEC sequence type 131 (ST131) as well as multiple sequence types in two distinct models of infection (colonization and bacteremia). SinH immunization also provided significant protection against ExPEC colonization in the bladder in an acute UTI model. Immunized cohorts produced significantly higher levels of vaccine-specific serum IgG and urinary IgG and IgA, findings consistent with mucosal protection. Collectively, these results demonstrate that autotransporter antigens such as SinH may constitute promising ExPEC phylogroup-specific and sequence-type effective vaccine targets that reduce E. coli colonization and virulence.

Metabolic profiling reveals nutrient preferences during carbon utilization in Bacillus species.

The genus Bacillus includes species with diverse natural histories, including free-living nonpathogenic heterotrophs such as B. subtilis and host-dependent pathogens such as B. anthracis (the etiological agent of the disease anthrax) and B. cereus, a cause of food poisoning. Although highly similar genotypically, the ecological niches of these three species are mutually exclusive, which raises the untested hypothesis that their metabolism has speciated along a nutritional tract. Here, we developed a pipeline for quantitative total assessment of the use of diverse sources of carbon for general metabolism to better appreciate the "culinary preferences" of three distinct Bacillus species, as well as related Staphylococcus aureus. We show that each species has widely varying metabolic ability to utilize diverse sources of carbon that correlated to their ecological niches. This approach was applied to the growth and survival of B. anthracis in a blood-like environment and find metabolism shifts from sugar to amino acids as the preferred source of energy. Finally, various nutrients in broth and host-like environments are identified that may promote or interfere with bacterial metabolism during infection.

Speckle tracking strain and ECG heterogeneity correlate in transcatheter aortic valve replacement-induced left bundle branch blocks and right ventricular paced rhythms.

OBJECTIVE: Transcatheter aortic valve replacement (TAVR) complications include left bundle branch block (LBBB) and right ventricular paced rhythm (RVP). We hypothesised that changes in electrocardiographic heterogeneity would correlate better with speckle tracking strain measures than with left ventricular ejection fraction (LVEF) on transthoracic echocardiogram (TTE) among patients with TAVR-induced conduction abnormalities. METHODS: We reviewed medical records of 446 consecutive patients who underwent TAVR at our institution. Of the 238 patients with 12-lead electrocardiograms (ECGs) that met our inclusion criteria, 58 had pre-TAVR and post-TAVR TTEs adequate for strain assessment. We compared patients who did not have an LBBB or RVP pre-TAVR and post-TAVR (controls, n=11) with patients who developed LBBBs (n=11) and who required RVPs (n=10) post-TAVR. In our study population (n=32, 41% female, mean age 85.8 years), we evaluated QRS complex duration, R-wave heterogeneity (RWH), T-wave heterogeneity (TWH), LVEF, global longitudinal strain (GLS) and mechanical dispersion (MD). RESULTS: TAVR-induced changes on ECG did not correlate with LVEF. TAVR-induced changes in MD and QRS complex duration correlated among all patients (r=0.4, p=0.04). GLS and RWH correlated among RVP patients (r=0.7, p=0.00003). MD and TWH correlated among LBBB patients (r=0.7, p=0.00004). CONCLUSIONS: In this convenience sample of patients with TAVR-induced conduction abnormalities, RWH and TWH correlated with strain measures but not with LVEF. Strain measures, RWH and TWH may offer additional insights for pre-TAVR evaluation and post-TAVR clinical management.

Preimplantation interlead ECG heterogeneity is superior to QRS complex duration in predicting mechanical super-response in patients with non-left bundle branch block receiving cardiac resynchronization therapy.

BACKGROUND: Reliable quantitative preimplantation predictors of response to cardiac resynchronization therapy (CRT) are needed. OBJECTIVE: We tested the utility of preimplantation R-wave and T-wave heterogeneity (RWH and TWH, respectively) compared to standard QRS complex duration in identifying mechanical super-responders to CRT and mortality risk. METHODS: We analyzed resting 12-lead electrocardiographic recordings from all 155 patients who received CRT devices between 2006 and 2018 at our institution and met class I and IIA American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines with echocardiograms before and after implantation. Super-responders (n=35, 23%) had ≥20% increase in left ventricular ejection fraction and/or ≥20% decrease in left ventricular end-systolic diameter and were compared with non-super-responders (n=120, 77%), who did not meet these criteria. RWH and TWH were measured using second central moment analysis. RESULTS: Among patients with non-left bundle branch block (LBBB), preimplantation RWH was significantly lower in super-responders than in non-super-responders in 3 of 4 lead sets (P=.001 to P=.038) and TWH in 2 lead sets (both, P=.05), with the corresponding areas under the curve (RWH: 0.810-0.891, P<.001; TWH: 0.759-0.810, P≤.005). No differences were observed in the LBBB group. Preimplantation QRS complex duration also did not differ between super-responders and non-super-responders among patients with (P=.856) or without (P=.724) LBBB; the areas under the curve were nonsignificant (both, P=.69). RWHV1-3LILII ≥ 420 µV predicted 3-year all-cause mortality in the entire cohort (P=.037), with a hazard ratio of 7.440 (95% confidence interval 1.015-54.527; P=.048); QRS complex duration ≥ 150 ms did not predict mortality (P=.27). CONCLUSION: Preimplantation interlead electrocardiographic heterogeneity but not QRS complex duration predicts mechanical super-response to CRT in patients with non-LBBB.

The Impact of Basal Septal Hypertrophy on Outcomes after Transcatheter Aortic Valve Replacement.

BACKGROUND: The role of basal septal hypertrophy (BSH) on preprocedural transthoracic echocardiography in transcatheter aortic valve replacement (TAVR) is unknown. METHODS: Medical charts and preprocedural transthoracic echocardiograms of 378 patients who underwent TAVR were examined. The association between BSH and the primary composite outcome of valve pop-out, recapture, embolization, aborted procedure, conversion to open procedure, new conduction disturbance, or need for permanent pacemaker ≤30 days after TAVR was evaluated. Patients with preexisting pacemakers were excluded. Sensitivity analyses were performed varying the definition of BSH. RESULTS: Of 296 TAVR patients (78.3%) with interpretable images, 55 (18.6%) had BSH at a median of 40 days (interquartile range, 19-62 days) before TAVR. Age and sex were similar among those with and without BSH. BSH patients received postdilation more frequently (BSH+ vs BSH-: 41.8% vs 29.9%, P = .04). A total of 50 individuals (16.9%) received pacemakers within 30 days, and 128 (43.2%) developed conduction disturbances (with left bundle branch block most common), without differences between groups. BSH was unrelated to the primary outcome on multivariate analysis (adjusted odds ratio BSH+ vs BSH-, 0.94; 95% CI, 0.42-2.11; P = .88). CONCLUSIONS: In this convenience sample of TAVR recipients at a large academic medical center, patients with BSH were more likely to receive postdilation. BSH was not associated with procedural or conduction outcomes after TAVR in patients without preexisting pacemakers.

Tricuspid Valve Dysfunction Caused by Right Ventricular Leads.

Tricuspid regurgitation is increasingly recognized as a clinically significant valvular condition. The role of multiple pacemaker and implantable cardiac defibrillator leads in distortion of the valve structure and the risk of trauma to the valve and subvalvular apparatus with lead extraction contribute to the development of tricuspid regurgitation (TR). There is a clinical imperative to better understand the optimal way to diagnose lead-related TR, risk factors for the development of TR, and optimal strategies to mitigate this problem.

Echocardiographic predictors of change in renal function with intravenous diuresis for decompensated heart failure.

AIMS: The aim of this study was to identify echocardiographic predictors of improved or worsening renal function during intravenous diuresis for decompensated heart failure. Secondary aim included defining the incidence and clinical risk factors for acute changes in renal function with decongestion. METHODS AND RESULTS: A retrospective review of 363 patients admitted to a single centre for decompensated heart failure who underwent intravenous diuresis and transthoracic echocardiography was conducted. Clinical, echocardiographic, and renal function data were retrospectively collected. A multinomial logistic regression model was created to determine relative risk ratios for improved renal function (IRF) or worsening renal function (WRF). Within this cohort, 36% of patients experienced WRF, 35% had stable renal function, and 29% had IRF. Patients with WRF were more likely to have a preserved left ventricular ejection fraction compared with those with stable renal function or IRF (P = 0.02). Patients with IRF were more likely to have a dilated, hypokinetic right ventricle compared with those with stable renal function or WRF (P ≤ 0.01), although this was not significant after adjustment for baseline characteristics. Left atrial size, left ventricular linear dimensions, and diastolic function did not significantly predict change in renal function. CONCLUSIONS: An acute change in renal function occurred in 65% of patients admitted with decompensated heart failure. WRF was statistically more likely in patients with a preserved left ventricular ejection fraction. A trend towards IRF was noted in patients with global right ventricular dysfunction.

Peptidoglycan Compositional Analysis of Enterococcus faecalis Biofilm by Stable Isotope Labeling by Amino Acids in a Bacterial Culture.

Peptidoglycan (PG) is a major component of the cell wall in Enterococcus faecalis. Accurate analysis of PG composition provides crucial insights into the bacterium's cellular functions and responses to external stimuli, but this analysis remains challenging because of various chemical modifications to PG-repeat subunits. We characterized changes to the PG composition of E. faecalis grown as planktonic bacteria and biofilm by developing "stable isotope labeling by amino acids in bacterial culture" (SILAB), optimized for bacterial cultures with incomplete amino acid labeling. This comparative analysis by mass spectrometry was performed by labeling E. faecalis in biofilm with heavy Lys (l-[13C6,2D9,15N2]Lys) and planktonic bacteria with natural abundance l-Lys, then mixing equal amounts of bacteria from each condition, and performing cell wall isolation and mutanolysin digestion necessary for liquid chromatography and mass spectrometry. An analytical method was developed to determine muropeptide abundances using correction factors to compensate for incomplete heavy Lys isotopic enrichment (98.33 ± 0.05%) and incorporation (83.23 ± 1.16%). Forty-seven pairs of PG fragment ions from isolated cell walls of planktonic and biofilm samples were selected for SILAB analysis. We found that the PG in biofilm showed an increased level of PG cross-linking, an increased level of N-deacetylation of GlcNAc, a decreased level of O-acetylation of MurNAc, and an increased number of stem modifications by d,d- and l,d-carboxypeptidases.

Inhibition of Staphylococcus aureus Cell Wall Biosynthesis by Desleucyl-Oritavancin: a Quantitative Peptidoglycan Composition Analysis by Mass Spectrometry.

Oritavancin is a lipoglycopeptide antibiotic that exhibits potent activities against vancomycin-resistant Gram-positive pathogens. Oritavancin differs from vancomycin by a hydrophobic side chain attached to the drug disaccharide, which forms a secondary binding site to enable oritavancin binding to the cross-linked peptidoglycan in the cell wall. The mode of action of secondary binding site was investigated by measuring the changes in the peptidoglycan composition of Staphylococcus aureus grown in the presence of desleucyl-oritavancin at subinhibitory concentration using liquid chromatography-mass spectrometry (LC-MS). Desleucyl-oritavancin is an Edman degradation product of oritavancin that exhibits potent antibacterial activities despite the damaged d-Ala-d-Ala binding site due to its functional secondary binding site. Accurate quantitative peptidoglycan composition analysis based on 83 muropeptide ions determined that cell walls of S. aureus grown in the presence of desleucyl-oritavancin showed a reduction of peptidoglycan cross-linking, increased muropeptides with a tetrapeptide-stem structure, decreased O-acetylation of MurNAc, and increased N-deacetylation of GlcNAc. The changes in peptidoglycan composition suggest that desleucyl-oritavancin targets the peptidoglycan template to induce cell wall disorder and interferes with cell wall maturation.IMPORTANCE Oritavancin is a lipoglycopeptide antibiotic with a secondary binding site that targets the cross-linked peptidoglycan bridge structure in the cell wall. Even after the loss of its primary d-Ala-d-Ala binding site through Edman degradation, desleucyl-oritavancin exhibits potent antimicrobial activities through its still-functioning secondary binding site. In this study, we characterized the mode of action for desleucyl-oritavancin's secondary binding site using LC-MS. Peptidoglycan composition analysis of desleucyl-oritavancin-treated S. aureus was performed by determining the relative abundances of 83 muropeptide ions matched from a precalculated library through integrating extracted ion chromatograms. Our work highlights the use of quantitative peptidoglycan composition analysis by LC-MS to provide insights into the mode of action of glycopeptide antibiotics.

Tricuspid Valve Dysfunction Following Pacemaker or Cardioverter-Defibrillator Implantation.

The potential for cardiac implantable electronic device leads to interfere with tricuspid valve (TV) function has gained increasing recognition as having hemodynamic and clinical consequences associated with incremental morbidity and death. The diagnosis and treatment of lead-related (as distinct from functional) tricuspid regurgitation pose unique challenges. Because of pitfalls in routine diagnostic imaging, a high level of clinical suspicion must be maintained to avoid overlooking the possibility that worsening heart failure is a consequence of mechanical interference with TV leaflet mobility or coaptation and is amenable to lead extraction or valve repair or replacement. The future of cardiac implantable electronic devices includes pacing and perhaps defibrillation without a lead traversing the TV.

Peptidoglycan O-acetylation increases in response to vancomycin treatment in vancomycin-resistant Enterococcus faecalis.

Vancomycin resistance is conferred upon vancomycin-resistant enterococci (VRE) through the replacement of peptidoglycan (PG) stem terminal d-Ala-d-Ala with d-Ala-d-Lac. The d-Ala-d-Lac incorporation can affect both the fitness and virulence of VRE. Here we comprehensively investigate the changes to PG composition in vancomycin-resistant Enterococcus faecalis following the growth in presence of vancomycin using liquid chromatography-mass spectrometry. Using high-resolution mass spectrometry, 104 unique muropeptides fragments were identified and the relative abundance of each fragment was accurately quantified by integrating the ion current of a selected ion using extracted-ion chromatogram. The analysis indicates reduced PG cross-linking, increased carboxypeptidase activities, increased N-deacetylation, and increased O-acetylation in VRE when grown in the presence of vancomycin. We found that O-acetylation preferentially occurred on muropeptides fragments with reduced cross-linking with a pentapeptide stem that terminated in d-Ala-d-Lac. These findings show that O-acetylation preferentially occurred in regions of the cell wall with reduced PG cross-linking on PG units that have stems terminating in d-Ala-d-Lac, serving as markers to prevent both the PG-stem modification by carboxypeptidases and the cell wall degradation by autolysins. Accurate quantitative PG composition analysis provided compositional insights into altered cell wall biosynthesis and modification processes in VRE that contribute to lysozyme resistance and enhanced virulence for VRE grown in the presence of vancomycin.

Quantification of the d-Ala-d-Lac-Terminated Peptidoglycan Structure in Vancomycin-Resistant Enterococcus faecalis Using a Combined Solid-State Nuclear Magnetic Resonance and Mass Spectrometry Analysis.

Induction of vancomycin resistance in vancomycin-resistant enterococci (VRE) involves replacement of the d-Ala-d-Ala terminus of peptidoglycan (PG) stems with d-Ala-d-Lac, dramatically reducing the binding affinity of vancomycin for lipid II. Effects from vancomycin resistance induction in Enterococcus faecalis (ATCC 51299) were characterized using a combined solid-state nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS) analysis. Solid-state NMR directly measured the total amounts of d-Lac and l,d-Ala metabolized from [2-13C]pyruvate, accumulated Park's nucleotide, and changes to the PG bridge-linking density during the early exponential growth phase (OD660 = 0.4) in intact whole cells of VRE. A high level of accumulation of depsipeptide-substituted Park's nucleotide consistent with the inhibition of the transglycosylation step of PG biosynthesis during the initial phase of vancomycin resistance was observed, while no changes to the PG bridge-linking density following the induction of vancomycin resistance were detected. This indicated that the attachment of the PG bridge to lipid II by the peptidyl transferases was not inhibited by the d-Ala-d-Lac-substituted PG stem structure in VRE. Compositions of mutanolysin-digested isolated cell walls of VRE grown with and without vancomycin resistance induction were determined by LC-MS. Muropeptides with PG stems terminating in d-Ala-d-Lac were found only in VRE grown in the presence of vancomycin. Percentages of muropeptides with a pentapeptide stem terminating in d-Ala-d-Lac for VRE grown in the presence of vancomycin were 26% for the midexponential phase (OD660 = 0.6) and 57% for the stationary growth phase (OD660 = 1.0). These high percentages indicate that d-Ala-d-Lac-substituted lipid II was efficiently utilized for PG biosynthesis in VRE.

Self-Expanding Transcatheter Aortic Valve Replacement Versus Surgical Valve Replacement in Patients at High Risk for Surgery: A Study of Echocardiographic Change and Risk Prediction.

BACKGROUND: The CoreValve US High-Risk Clinical Study compared clinical outcomes and serial echocardiographic findings in patients with severe aortic valve stenosis after transcatheter aortic valve replacement (TAVR) with a self-expanding bioprosthesis or surgical aortic valve replacement (SAVR). METHODS AND RESULTS: Eligible patients were randomly assigned 1:1 to TAVR with a self-expanding bioprosthesis or SAVR (N=747). Echocardiograms were obtained at baseline, discharge, 30 days, 6 months, and 1 year after the procedure and were analyzed at a central core laboratory. Compared with SAVR patients (N=357), TAVR patients (N=390) had a lower mean aortic valve gradient, larger valve area, and less patient-prosthesis mismatch (all P<0.001), but more paravalvular regurgitation at discharge, which decreased at 1 year. SAVR patients experienced significant right ventricular systolic dysfunction at discharge and 1 month with normal right ventricular function at 1 year. One-year all-cause mortality was 14.2% for TAVR and 19.1% for SAVR patients. Preimplantation aortic regurgitation ≥mild was associated with reduced mortality hazard for both the TAVR (hazard ratio 0.48, 95% confidence interval 0.27-0.85; P=0.01) and the SAVR groups (hazard ratio 0.53, 95% confidence interval 0.32-0.87; P=0.01). Aortic regurgitation ≥mild after TAVR was associated with increased risk for all-cause mortality (hazard ratio 1.95, 95% confidence interval 1.08-3.53; P=0.03). CONCLUSIONS: In patients with severe aortic stenosis at increased surgical risk, TAVR was associated with better systolic valve performance, similar left ventricular remodeling, more paravalvular regurgitation, and less right ventricular systolic dysfunction compared with SAVR. Despite an overall mortality reduction for the TAVR group, ≥mild aortic valve regurgitation after TAVR was associated with an increased mortality hazard. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01240902.

Tricuspid Regurgitation and Mortality in Patients With Transvenous Permanent Pacemaker Leads.

Estimates of the prevalence and importance of significant tricuspid regurgitation (STR) related to implantable device leads are based mainly on case reports, small observational studies, or mixed samples that include defibrillators. We sought to assess whether patients with permanent pacemaker (PPM) leads have an increased risk of STR and to determine mortality associated with PPM-related TR in a large longitudinal single-center cohort. We examined the prevalence of STR (defined as moderate-severe or ≥3+) among all echocardiograms performed from 2005 to 2011 excluding those with defibrillators. We then examined mortality risk according to the prevalence of PPM and STR after adjusting for cardiac co-morbidities, left ventricular systolic/diastolic function, and pulmonary artery hypertension. We screened 93,592 echocardiograms (1,245 with PPM) in 58,556 individual patients (634 with PPM). The prevalence of STR was higher in patients after PPM placement (mean age 79 ± 3 years; 54% men) compared with those without a PPM (adjusted odds ratio 2.32; 95% confidence interval [CI] 1.54 to 3.49; p <0.0001). Among patients with a PPM lead, the presence of STR was associated with increased mortality (adjusted hazard ratio 1.40; 95% CI 1.04 to 2.11, p = 0.027, vs no STR). Compared with having neither a PPM lead nor STR, adjusted hazard ratios for death were 2.13 (95% CI 1.93 to 2.34) for STR but no PPM, 1.04 (0.89 to 1.22) for PPM without STR, and 1.55 (1.13 to 2.14) for PPM with STR. In conclusion, in a sample comprising >58,000 individual patients, PPM leads are associated with higher risk of STR after adjustment for left ventricular systolic/diastolic function and pulmonary artery hypertension; similarly to STR from other cardiac pathologies, PPM-related STR is associated with increased mortality.

Chemotherapy-induced cardiomyopathy.

Cardiomyopathy is an adverse outcome of antineoplastic drug therapy that has become increasingly relevant in the management of cancer survivors. As the efficacy of anticancer treatments has improved, long-term outcomes are altered by the development of cardiotoxicity, which may be associated with an even worse prognosis than that of the underlying malignancy. From the research into mechanisms, prevention, and treatment, the specialized field of cardio-oncology has evolved, but the recognition and appropriate management of these patients is important for the general internist and general cardiologist as well. Although antineoplastic chemotherapy can cause multiple forms of cardiotoxicity, including arrhythmia, pericardial disease, valvular dysfunction, and myocardial ischemia, in this review we will focus on chemotherapeutic agents associated with cardiomyopathies, from the anthracyclines to newer, the so-called targeted agents such as tyrosine kinase inhibitors. We also review the diagnostic modalities for chemotherapy-induced cardiomyopathy as well as the prevention and treatment strategies which may prolong the lives of those suffering from cancer.

Primary cardiac burkitt lymphoma presenting with abdominal pain.

We describe the case of a 44-year-old woman with primary Burkitt lymphoma of the heart who presented with abdominal bloating and epigastric discomfort secondary to tamponade physiology caused by a large pericardial effusion. The pericardial fluid contained a large number of highly atypical lymphocytes with moderate basophilic cytoplasm, rare punched-out vacuoles, a vesicular nuclear chromatin, large nucleolus, and marginated chromatin that by FISH were positive for the 8;14 translocation. She had no other sites of disease. She was treated with four alternating cycles of modified CODOX-M and IVAC in combination with rituximab and remains in remission more than 5 years since diagnosis.

Derivation and validation of a 30-day heart failure readmission model.

In 2006, there were >1 million hospital admissions for heart failure (HF), and the estimated cost to the United States in 2009 was >$37.2 billion. Better models to target aggressive therapy to patients at the highest risk for readmission are clearly needed. We studied 3,413 consecutive admissions for HF based on discharge diagnosis codes from October 2007 to August 2011 from a single academic center. We randomly generated derivation and validation sets in a 3:1 ratio. We used generalized estimating equations to develop our models, accounting for repeated hospitalizations and the Hosmer-Lemeshow test to examine model calibration. The 30-day readmission rate was 24.2% in the derivation set. Of 25 candidate variables, the best fitting model included creatinine, troponin, hematocrit, and hyponatremia at discharge; race; zip code of residence; discharge hour; and number of hospitalizations in the previous year. Insignificant variables included intravenous diuretic use on day of discharge, discharge service, diabetes, atrial fibrillation, age, and gender. The risk of 30-day readmission increased with increasing decile of predicted risk in both the validation and derivation cohorts. The area under the receiver operating characteristic curve for the model was 0.69 in the derivation set and 0.66 in the validation set. In conclusion, we derived and validated a simple model relating discharge-specific characteristics at risk of 30-day readmission. Application of this approach may facilitate targeted intervention to reduce the burden of rehospitalization in patients with HF, but our results suggest that the best readmission models may require incorporation of both clinical and local system factors for optimal prediction.