All-Cause Mortality and Progression Risks to Hepatic Decompensation and Hepatocellular Carcinoma in Patients Infected With Hepatitis C Virus.

BACKGROUND: A key question in care of patients with chronic hepatitis C virus (HCV) infection is beginning treatment immediately vs delaying treatment. Risks of mortality and disease progression in "real world" settings are important to assess the implications of delaying HCV treatment. METHODS: This was a cohort study of HCV patients identified from 4 integrated health systems in the United States who had liver biopsies during 2001-2012. The probabilities of death and progression to hepatocellular carcinoma, hepatic decompensation (hepatic encephalopathy, esophageal varices, ascites, or portal hypertension) or liver transplant were estimated over 1, 2, or 5 years by fibrosis stage (Metavir F0-F4) determined by biopsy at beginning of observation. RESULTS: Among 2799 HCV-monoinfected patients who had a qualifying liver biopsy, the mean age at the time of biopsy was 50.7 years. The majority were male (58.9%) and non-Hispanic white (66.9%). Over a mean observation of 5.0 years, 261 (9.3%) patients died and 34 (1.2%) received liver transplants. At 5 years after biopsy, the estimated risk of progression to hepatic decompensation or hepatocellular carcinoma was 37.2% in stage F4, 19.6% in F3, 4.7% in F2, and 2.3% in F0-F1 patients. Baseline biopsy stage F3 or F4 and platelet count below normal were the strongest predictors of progression to hepatic decompensation or hepatocellular carcinoma. CONCLUSIONS: The risks of death and progression to liver failure varied greatly by fibrosis stage. Clinicians and policy makers could use these progression risk data in prioritization and in determining the timing of treatment for patients in early stages of liver disease.

The Michigan Spine Surgery Improvement Collaborative: a statewide Collaborative Quality Initiative.

OBJECT Given the scrutiny of spine surgery by policy makers, spine surgeons are motivated to demonstrate and improve outcomes, by determining which patients will and will not benefit from surgery, and to reduce costs, often by reducing complications. Insurers are similarly motivated. In 2013, Blue Cross Blue Shield of Michigan (BCBSM) and Blue Care Network (BCN) established the Michigan Spine Surgery Improvement Collaborative (MSSIC) as a Collaborative Quality Initiative (CQI). MSSIC is one of the newest of 21 other CQIs that have significantly improved-and continue to improve-the quality of patient care throughout the state of Michigan. METHODS MSSIC focuses on lumbar and cervical spine surgery, specifically indications such as stenosis, disk herniation, and degenerative disease. Surgery for tumors, traumatic fractures, deformity, scoliosis, and acute spinal cord injury are currently not within the scope of MSSIC. Starting in 2014, MSSIC consisted of 7 hospitals and in 2015 included another 15 hospitals, for a total of 22 hospitals statewide. A standardized data set is obtained by data abstractors, who are funded by BCBSM/BCN. Variables of interest include indications for surgery, baseline patient-reported outcome measures, and medical history. These are obtained within 30 days of surgery. Outcome instruments used include the EQ-5D general health state score (0 being worst and 100 being the best health one can imagine) and EQ-5D-3 L. For patients undergoing lumbar surgery, a 0 to 10 numeric rating scale for leg and back pain and the Oswestry Disability Index for back pain are collected. For patients undergoing cervical surgery, a 0 to 10 numeric rating scale for arm and neck pain, Neck Disability Index, and the modified Japanese Orthopaedic Association score are collected. Surgical details, postoperative hospital course, and patient-reported outcome measures are collected at 90-day, 1-year, and 2-year intervals. RESULTS As of July 1, 2015, a total of 6397 cases have been entered into the registry. This number reflects 4824 eligible cases with confirmed surgery dates. Of these 4824 eligible cases, 3338 cases went beyond the 120-day window and were considered eligible for the extraction of surgical details, 90-day outcomes, and adverse events. Among these 3338 patients, there are a total of 2469 lumbar cases, 862 cervical cases, and 7 combined procedures that were entered into the registry. CONCLUSIONS In addition to functioning as a registry, MSSIC is also meant to be a platform for quality improvement with the potential for future initiatives and best practices to be implemented statewide in order to improve quality and lower costs. With its current rate of recruitment and expansion, MSSIC will provide a robust platform as a regional prospective registry. Its unique funding model, which is supported by BCBSM/BCN, will help ensure its longevity and viability, as has been observed in other CQIs that have been active for several years.

Prevalence of cirrhosis in hepatitis C patients in the Chronic Hepatitis Cohort Study (CHeCS): a retrospective and prospective observational study.

OBJECTIVES: The severity of liver disease in the hepatitis C virus (HCV)-infected population in the United States remains uncertain. We estimated the prevalence of cirrhosis in adults with chronic hepatitis C (CHC) using multiple parameters including liver biopsy, diagnosis/procedure codes, and a biomarker. METHODS: Patients enrolled in the Chronic Hepatitis Cohort Study (CHeCS) who received health services during 2006-2010 were included. Cirrhosis was identified through liver biopsy reports, diagnosis/procedure codes for cirrhosis or hepatic decompensation, and Fibrosis-4 (FIB-4) scores ≥5.88. Demographic and clinical characteristics associated with cirrhosis were identified through multivariable logistic modeling. RESULTS: Among 9,783 patients, 2,788 (28.5%) were cirrhotic by at least one method. Biopsy identified cirrhosis in only 661 (7%) patients, whereas FIB-4 scores and diagnosis/procedure codes for cirrhosis and hepatic decompensation identified cirrhosis in 2,194 (22%), 557 (6%), and 482 (5%) patients, respectively. Among 661 patients with biopsy-confirmed cirrhosis, only 356 (54%) had an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for cirrhosis. Older age, male gender, Asian race, Hispanic ethnicity, genotype 3 infection, HIV coinfection, diabetes, history of antiviral therapy, and history of alcohol abuse were independently associated with higher odds of cirrhosis (all, P<0.05). Conversely, private health insurance coverage, black race, and HCV genotype 2 were associated with lower odds of cirrhosis. CONCLUSIONS: A high proportion of patients with biopsy-confirmed cirrhosis are not assigned ICD-9 codes for cirrhosis. Consequently, ICD-9 codes may not be reliable as the sole indicator of the prevalence of cirrhosis in cohort studies. Use of additional parameters suggests a fourfold higher prevalence of cirrhosis than is revealed by biopsy alone. These findings suggest that cirrhosis in CHC patients may be significantly underdocumented and underdiagnosed.

Physician use of persuasion and colorectal cancer screening.

The impact of patient-physician communication on subsequent patient behavior has rarely been evaluated in the context of colorectal cancer (CRC) screening discussions. We describe physicians' use of persuasive techniques when recommending CRC screening and evaluate its association with patients' subsequent adherence to screening. Audio recordings of N = 414 periodic health examinations were joined with screening use data from electronic medical records and pre-/post-visit patient surveys. The association between persuasion and screening was assessed using generalized estimating equations. According to observer ratings, primary care physicians frequently use persuasive techniques (63 %) when recommending CRC screening, most commonly argument or refutation. However, physician persuasion was not associated with subsequent screening adherence. Physician use of persuasion may be a common vehicle for information provision during CRC screening discussions; however, our results do not support the sole reliance on persuasive techniques if the goal is to improve adherence to recommended screening.

Prospective randomized phase 2 trial of intensity modulated radiation therapy with or without oncolytic adenovirus-mediated cytotoxic gene therapy in intermediate-risk prostate cancer.

PURPOSE: To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer. METHODS AND MATERIALS: Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival. RESULTS: Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the 2 arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer. CONCLUSIONS: Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer.

Patient-physician colorectal cancer screening discussion content and patients' use of colorectal cancer screening.

OBJECTIVE: The US Preventive Services Task Force recommends using the 5As (i.e., Assess, Advise, Agree, Assist and Arrange) when discussing preventive services. We evaluate the association of the 5As discussion during primary care office visits with patients' subsequent colorectal cancer (CRC) screening use. METHODS: Audio-recordings of n=443 periodic health exams among insured patients aged 50-80 years and due for CRC screening were joined with pre-visit patient surveys and screening use data from an electronic medical record. Association of the 5As with CRC screening was assessed using generalized estimating equations. RESULTS: 93% of patients received a recommendation for screening (Advise) and 53% were screened in the following year. The likelihood of screening increased as the number of 5A steps increased: compared to patients whose visit contained no 5A step, those whose visit contained 1-2 steps (OR=2.96 [95% CI 1.16, 7.53]) and 3 or more steps (4.98 [95% CI 1.84, 13.44]) were significantly more likely to use screening. CONCLUSIONS: Physician CRC screening recommendations that include recommended 5A steps are associated with increased patient adherence. PRACTICE IMPLICATIONS: A CRC screening recommendation (Advise) that also describes patient eligibility (Assess) and provides help to obtain screening (Assist) may lead to improved adherence to CRC screening.

Antiviral therapy for chronic hepatitis B virus infection and development of hepatocellular carcinoma in a US population.

BACKGROUND & AIMS: Antiviral therapy could reduce the risk of hepatocellular carcinoma (HCC) among persons with chronic hepatitis B virus (HBV) infection. We evaluated the relationship between therapy for chronic HBV infection and HCC incidence using data from a longitudinal study of patients at 4 US healthcare centers. METHODS: We analyzed electronic health records of 2671 adult participants in the Chronic Hepatitis Cohort Study who were diagnosed with chronic HBV infection from 1992 through 2011 (49% Asian). Data analyzed were collected for a median of 5.2 years. Propensity-score adjustment was used to reduce bias, and Cox regression was used to estimate the relationship between antiviral treatment and HCC. The primary outcome was time to event of HCC incidence. RESULTS: Of study subjects, 3% developed HCC during follow-up period: 20 cases among the 820 patients with a history of antiviral HBV therapy and 47 cases among the 1851 untreated patients. In propensity-adjusted Cox regression, patients who received antiviral therapy had a lower risk of HCC than those who did not receive antiviral therapy (adjusted hazard ratio, 0.39; 95% confidence interval, 0.27-0.56; P < .001), after adjusting for abnormal level of alanine aminotransferase. In a subgroup analysis, antiviral treatment was associated with a lower risk of HCC after adjusting for serum markers of cirrhosis (adjusted hazard ratio, 0.24; 95% confidence interval, 0.15-0.39; P < .001). In a separate subgroup analysis of patients with available data on HBV DNA viral load, treated patients with viral loads >20,000 IU/mL had a significantly lower risk of HCC than untreated patients with viral loads >20,000 IU/mL. CONCLUSIONS: In a large geographically, clinically, and racially diverse US cohort, antiviral therapy for chronic HBV infection was associated with a reduced risk for HCC.

Baseline characteristics and mortality among people in care for chronic viral hepatitis: the chronic hepatitis cohort study.

BACKGROUND: The Chronic Hepatitis Cohort Study (CHeCS), a dynamic prospective, longitudinal, observational cohort study, was created to assess the clinical impact of chronic viral hepatitis in the United States. This report describes the cohort selection process, baseline demographics, and insurance, biopsy, hospitalization, and mortality rates. METHODS: Electronic health records of >1.6 million adult patients seen from January 2006 through December 2010 at 4 integrated healthcare systems in Detroit, Michigan; Danville, Pennsylvania; Portland, Oregon; and Honolulu, Hawaii were collected and analyzed. RESULTS: Of 2202 patients with chronic hepatitis B virus (HBV) infection, 50% were aged 44-63 years, 57% male, 58% Asian/Pacific Islander, and 13% black; and 5.1% had Medicaid, 16.5% Medicare, and 76.3% private insurance. During 2001-2010, 22.3% had a liver biopsy and 37.9% were hospitalized. For the 8810 patients with chronic hepatitis C virus (HCV) infection, 75% were aged 44-63 years, 60% male, 23% black; and 12% had Medicaid, 23% Medicare, and 62% private insurance. During 2001-2010, 38.4% had a liver biopsy and 44.3% were hospitalized. Among persons in care, 9% of persons with HBV and 14% of persons with HCV infection, mainly those born during 1945-1964, died during the 2006-2010 five-year period. CONCLUSIONS: Baseline demographic, hospitalization, and mortality data from CHeCS highlight the substantial US health burden from chronic viral hepatitis, particularly among persons born during 1945-1964.

Patient-physician colorectal cancer screening discussions: delivery of the 5A's in practice.

BACKGROUND: The U.S. Preventive Services Task Force advocates use of a 5A's framework (assess, advise, agree, assist, and arrange) for preventive health recommendations. PURPOSE: To describe 5A content of patient-physician colorectal cancer (CRC) screening discussions and physician-recommended screening modality and to test if these vary by whether patient previously received screening recommendation. METHODS: Direct observation of periodic health examinations in 2007-2009 among average-risk primary care patients aged 50-80 years due for screening. Qualitative content analyses conducted 2008-2010 used to code office visit audio-recordings for 5A and other discussion content. RESULTS: Among study-eligible visits (N=415), 59% contained assistance (i.e., help scheduling colonoscopy or delivery of stool cards), but the assess, advise, and agree steps were rarely comprehensively provided (1%-21%), and only 3% included the last step, arrange follow-up. Almost all physicians endorsed screening via colonoscopy (99%), either alone (69%) or in combination with other tests (30%). Patients nonadherent to a prior physician screening recommendation (31%) were less likely to have the reason(s) for screening discussed (37% vs 65%) or be told the endoscopy clinic would call them for scheduling (19% vs 27%), and more likely to have fecal occult blood testing (FOBT) alone (34% vs 25%) or FOBT and colonoscopy recommended (24% vs 14%), and a screening plan negotiated (21% vs 14%). Significance level is p<0.05 for all contrasts. CONCLUSIONS: Most patients due for CRC screening discuss screening with their physician, but with limited application of the 5A's approach. Opportunities to improve CRC screening decision-making are great, particularly among patients who are nonadherent to a prior recommendation from a physician.

Patient-rated importance and receipt of information for colorectal cancer screening.

BACKGROUND: Physician recommendation is one of the most important determinants of obtaining colorectal cancer (CRC) screening; however, little is known about the degree to which CRC screening discussions include information that patients report as important to guide screening decisions. This study examines and compares both patient rated importance and physician communication of key information elements about CRC screening during annual physical examinations. DESIGN: Cross-sectional cohort. SETTING: 26 ambulatory clinics of an integrated delivery system in the Midwest. PARTICIPANTS: 64 primary care physicians and 415 patients aged 50 to 80 due for CRC screening. Patients completed a previsit survey to assess importance of specific information when making a preventive screening decision. Visits were audio recorded to assess the content of screening discussions. RESULTS: Most patients rated test accuracy (85%), testing alternatives (83%), the pros and cons of testing (86%), and the testing process (78%) very important when making preventive screening decisions. Ninety-one percent of visits included a CRC screening discussion; however, CRC screening talk rarely included information that patients rated as important. Physicians infrequently asked whether patients had questions pertaining to CRC screening (5%); however, 49% of patients asked a CRC screening question, with the vast majority pertaining to screening logistics. CONCLUSIONS: Audio recordings confirm that discussions of CRC screening are often lacking information that patients indicate is very important when making preventive health decisions and patient questions during the visit are not eliciting information to fill the gap. IMPACT: These findings provide actionable information to improve CRC screening discussions.

Inconsistencies in patient perceptions and observer ratings of shared decision making: the case of colorectal cancer screening.

OBJECTIVE: To compare patient-reported and observer-rated shared decision making (SDM) use for colorectal cancer (CRC) screening and evaluate patient, physician and patient-reported relational communication factors associated with patient-reported use of shared CRC screening decisions. METHODS: Study physicians are salaried primary care providers. Patients are insured, aged 50-80 and due for CRC screening. Audio-recordings from 363 primary care visits were observer-coded for elements of SDM. A post-visit patient survey assessed patient-reported decision-making processes and relational communication during visit. Association of patient-reported SDM with observer-rated elements of SDM, as well as patient, physician and relational communication factors were evaluated using generalized estimating equations. RESULTS: 70% of patients preferred SDM for preventive health decisions, 47% of patients reported use of a SDM process, and only one of the screening discussions included all four elements of SDM per observer ratings. Patient report of SDM use was not associated with observer-rated elements of SDM, but was significantly associated with female physician gender and patient-reported relational communication. CONCLUSION: Inconsistencies exist between patient reports and observer ratings of SDM for CRC screening. PRACTICE IMPLICATIONS: Future studies are needed to understand whether SDM that is patient-reported, observer-rated or both are associated with informed and value-concordant CRC screening decisions.

Predicting final infarct size using acute and subacute multiparametric MRI measurements in patients with ischemic stroke.

PURPOSE: To identify early MRI characteristics of ischemic stroke that predict final infarct size three months poststroke. MATERIALS AND METHODS: Multiparametric MRI (multispin echo T2-weighted [T2W] imaging, T1-weighted [T1W] imaging, and diffusion-weighted imaging [DWI]) was performed acutely (<24 hours), subacutely (three to five days), and at three months. MRI was processed using maps of apparent diffusion coefficient (ADC), T2, and a self-organizing data analysis (ISODATA) technique. Analyses began with testing for individual MRI parameter effects, followed by multivariable modeling with assessment of predictive ability (R(2)) on final infarct size. RESULTS: A total of 45 patients were studied, 15 of whom were treated with tissue plasminogen activator (tPA) before acute MRI. The acute DWI and DWI-ISODATA mismatch lesion size, and the interactions of ADC, T2, and T2W imaging lesion with tPA remained in the final multivariable model (R(2) = 70%). A large acute DWI lesion or DWI < ISODATA lesion independently predicted increase in the final infract size, with predictive ability 68%. Predictive ability increased (R(2) = 83%) when subacute MRI parameters were included along with acute DWI, DWI-ISODATA mismatch, and acute T2W image lesion size by tPA treatment interaction. Subacute DWI > acute DWI lesion size predicted an increased final infarct size (P < 0.01). CONCLUSION: Acute-phase DWI and DWI-ISODATA mismatch strongly predict the final infarct size. An acute-to-subacute DWI lesion size change further increases the predictive ability of the model.

Gene transfer of NAD(P)H oxidase inhibitor to the vascular adventitia attenuates medial smooth muscle hypertrophy.

We previously showed that a systemic inhibitor of gp91(phox) (nox2)-based NAD(P)H oxidase abolishes angiotensin II (Ang II)-induced vascular hypertrophy. In the present study, we tested whether perivascular transfection with Ad-gp91ds-eGFP (an adenoviral bicistronic construct targeting NAD(P)H oxidase in fibroblasts) or controls Ad-CMV-eGFP and Ad-scrmb-eGFP would affect medial hypertrophy in response to Ang II. In C57BL/6J mice, we applied Ad-gp91ds-eGFP or controls to the left carotid adventitia, and 2 days later we implanted minipumps delivering vehicle or Ang II (750 microg/kg per day) for 7 days. None of the viral treatments affected Ang II-induced systolic blood pressure elevation. Immunohistochemical staining showed marker eGFP in adventitial fibroblasts and some macrophages, indicating expression of the gp91ds inhibitor. As expected, Ang II induced medial hypertrophy (medial cross-sectional area, 32.96+/-2.04 versus 20.57+/-1.00x10(3) microm2, Ang II versus control; P<0.001) that was significantly inhibited by Ad-gp91ds-eGFP (26.23+/-0.90x10(3) microm2; P<0.01) but not control viruses. Application of viruses alone did not change medial size under control conditions. Immunohistochemical staining and semiquantitative analysis showed a 70% increase in reactive oxygen species levels measured by the lipid peroxidation byproduct 4-hydroxynonenal (4-HNE) throughout the carotid wall in the Ang II group versus vehicle. After treatment with Ad-gp91ds-eGFP, 4-HNE generation was normalized. Thus NAD(P)H oxidases in adventitial fibroblasts and macrophages appear to modulate Ang II-induced medial hypertrophy.

Dual inhibition of ACE and NEP provides greater cardioprotection in mice with heart failure.

BACKGROUND: Vasopeptidase inhibitors (VPi) may provide a new means of treating hypertension and congestive heart failure, because they simultaneously block angiotensin-converting enzyme (ACE) and neutral endopeptidase-24.11 (NEP-24.11), thereby inhibiting the renin-angiotensin system and enhancing vasodilator and natriuretic substances such as kinins and natriuretic peptides. METHODS: Using B(2) kinin receptor gene knockout mice (B(2)-/-), we tested the hypotheses that (1) VPi may provide better cardioprotection than ACE or NEP inhibitors alone (ACEi and NEPi) and (2) the effects of these inhibitors are partially mediated by kinins. Four weeks after myocardial infarction, B(2)-/- mice and B(2)+/+ mice were started on vehicle, ACEi (ramipril, 2.5 mg/kg/d), NEPi (candoxatril, 20 mg/kg/d) or VPi (omapatrilat, 50 mg/kg/d), which was continued for 20 weeks. Systolic blood pressure was measured weekly and cardiac function evaluated monthly by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were measured histopathologically. RESULTS: We found that ACEi or NEPi improved cardiac function and remodeling and that these effects were more obvious in mice receiving VPi. Furthermore, the beneficial cardiac effects of ACEi, NEPi, and VPi were significantly attenuated in B(2)-/- mice. We concluded that dual inhibition of ACE and NEP with VPi provides better cardioprotection than ACEi or NEPi alone in mice with congestive heart failure induced by myocardial infarction, and these effects are mediated at least in part via kinins.

Ac-SDKP reverses cardiac fibrosis in rats with renovascular hypertension.

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural substrate for the N-terminal active site of angiotensin-converting enzyme (ACE). We previously reported that Ac-SDKP prevented cardiac fibrosis in rats with renovascular or aldosterone-salt hypertension. However, it is not clear whether Ac-SDKP reverses cardiac fibrosis in hypertension, nor the mechanism(s) involved. In the present study, we tested the hypothesis that Ac-SDKP reversal of hypertension-induced cardiac fibrosis involves a decrease in transforming growth factor-beta (TGF-beta) and/or connective tissue growth factor (CTGF). In 2-kidney, 1-clip (2K-1C) hypertensive rats, Ac-SDKP at 400 or 800 microg/kg per day SC was started 8 weeks after hypertension and cardiac fibrosis were established and was continued for 8 weeks. Left ventricular (LV) collagen in rats with 2K-1C plus vehicle at 8 and 16 weeks after clipping was similar but higher than in the sham group (P<0.05). Ac-SDKP at 400 and 800 microg/kg per day, which increased plasma Ac-SDKP 2- and 5-fold, respectively, reversed the increase in LV collagen in a dose-dependent manner. The mechanism by which Ac-SDKP reverses LV fibrosis does not appear to depend on ACE inhibition by Ac-SDKP, since we found that Ac-SDKP at various doses did not affect blood pressure responses to exogenous angiotensin I or bradykinin. However, Ac-SDKP reversed the increase in LV TGF-beta and CTGF compared with rats with 2K-1C plus vehicle (P<0.005). We concluded that in hypertension, Ac-SDKP reverses cardiac fibrosis, perhaps due in part to a decrease in TGF-beta and CTGF in the heart.

Long-term effects of selective and nonselective endothelin receptor antagonists in mice with heart failure.

BACKGROUND: The ET(A) and ET(B) receptors mediate vasoconstriction, aldosterone release, and fibrosis. However, the role of ET(B) receptors is still controversial because those expressed on endothelial cells also stimulate vasodilatation and may oppose the actions of the ET(A) receptor. Plasma levels of endothelin-1 (ET-1) are increased in heart failure (HF) and are associated with myocardial dysfunction. The relative efficacy of selective and nonselective ET antagonists in the treatment of HF is unclear. We hypothesized that blockade of ET(A) receptors may improve cardiac function and prevent left ventricular remodeling in mice with HF, and these effects may be mediated in part by activation of ET(B). METHODS AND RESULTS: A mouse model of chronic HF induced by myocardial infarction (MI) was used. Seven days after MI, mice were divided into vehicle, ET(A)-ant, or ET(A/B)-ant groups and treated for 23 weeks. Cardiac function, LV dimensions, and hemodynamics were evaluated in conscious mice before MI and during treatment. Histologic analysis of the heart and liver was performed at the end of the study. HF significantly decreased EF and increased LV dimensions, interstitial collagen fraction (ICF) and myocyte cross-sectional area (MCSA). Both ET(A)-ant and ET(A/B)-ant slightly increased EF but had no significant effect on LV dimensions, hypertrophy, or ICF. Both treatments decreased MCSA; however, this was only significant in the ET(A/B)-ant group. CONCLUSIONS: Both selective and nonselective ET-ant have similar slight effects on cardiac function and remodeling. This suggests that (1) ET(B) receptors do not mediate the beneficial cardiac effects of ET(A)-ant and (2) blockade of the ET system alone may not provide significant cardioprotection, at least in mice with HF induced by MI.