Lack of Association Between Neurohormonal Blockade and Survival in Transthyretin Cardiac Amyloidosis.

Background Despite the belief that heart failure therapies are not effective in transthyretin cardiac amyloidosis, data are limited. We tested the association of neurohormonal blockade use with survival. Methods and Results A total of 309 consecutive patients with transthyretin cardiac amyloidosis were identified. Medication inventory was obtained at baseline and subsequent visits. Exposure included a neurohormonal blockade class (ß-blocker [ßB], angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and mineralocorticoid antagonist) at baseline and subsequent visits. ßB was modeled as baseline use, time-varying use, and in an inverse probability treatment weighted model. Primary outcome was all-cause mortality analyzed with adjusted Cox proportional hazards models. Continuing compared with stopping ßB during follow-up was tested. Mean age was 73.2 years, 84.1% were men, and 17.2% had atrial fibrillation/flutter at baseline. At the time of study entry, 49.8% were on ßBs, 35.0% were on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 23.9% were on mineralocorticoid antagonists. For the total cohort, there was a trend toward harm in the unadjusted model for baseline ßB use, but this was neutral after adjustment. When ßB use was analyzed as a time-varying exposure, there was no association with mortality. ßB discontinuation was associated with decreased mortality for the total cohort. Findings were consistent in inverse probability treatment weighted models. For angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or mineralocorticoid antagonist use, there was no association with mortality after adjustment for the total cohort. Conclusions There was no association of neurohormonal blockade use with survival in transthyretin cardiac amyloidosis. For the total cohort, deprescribing ßB may be associated with improved survival. Additional studies are needed to confirm these findings.

Treating symptoms and reversing remodelling: clinical and echocardiographic 1-year outcomes with percutaneous mitral annuloplasty for mild to moderate secondary mitral regurgitation.

AIMS: To determine the effects of percutaneous mitral annuloplasty on symptoms, walk distance and left ventricular (LV) structure and function in patients with mild or moderate secondary mitral regurgitation (SMR). METHODS AND RESULTS: This was a pooled analysis of patients (n = 68) who, despite guideline-directed medical therapy had symptomatic heart failure (HF) with mild (n = 25) or moderate (n = 43) SMR treated with percutaneous mitral annuloplasty as part of the TITAN, TITAN II, or REDUCE-FMR trials. Primary outcomes were changes in symptoms, 6-min walk distance, and quality of life assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) after 1 year. Secondary analyses included changes in LV structure and function. At 1 year, New York Heart Association class status was maintained (48%) or improved (46%) in most patients, mean KCCQ scores increased from baseline by 10 units [95% confidence interval (CI) 3 to17; P < 0.01] and mean 6-min walk test distance increased by 34 m (95% CI 12 to 57; P < 0.01). SMR grade improved in 25% of patients and was maintained in 58% of patients with changes in mean regurgitant volume of -7 mL (95% CI -11 to -3; P < 0.001), vena contracta -0.11 cm (95% CI -0.20 to -0.02; P < 0.05), and effective regurgitant orifice area -0.03 cm2 (95% CI -0.06 to -0.01; P < 0.05). There were non-significant improvements in LV ejection fraction and volumes. Survival over 1 year was 89% with no difference between mild (96%) and moderate (86%) SMR (log-rank P = 0.22). Progression-free survival was 70% (82% in mild vs. 63% in moderate SMR; P = 0.16). Freedom from HF hospitalization was 73% (87% in mild SMR vs. 66% in moderate SMR; P = 0.07). CONCLUSION: Among patients with symptomatic HF and mild or moderate SMR on guideline-directed medical therapy, percutaneous mitral annuloplasty was associated with improvements in symptoms, SMR, a stabilization of LV structure and function, and high survival rates.

The association between heart failure and incident cancer in women: an analysis of the Women's Health Initiative.

AIMS: There is conflicting evidence whether heart failure (HF) is a risk factor for incident cancer. Despite population-based cohorts demonstrating this association, an analysis of the Physician's Health Study found no association in a cohort of mostly healthy males. We investigated the association of HF with incident cancer among a large cohort of post-menopausal women. METHODS AND RESULTS: A prospective cohort study of 146 817 post-menopausal women age 50 to 79 years enrolled in the Women's Health Initiative from 1993-1998, and followed through 2015. The primary exposure was adjudicated incident HF diagnosis, including preserved and reduced ejection fraction in a sub-cohort. The primary outcome was adjudicated incident total and site-specific cancers. Hazard ratios were calculated using multivariable-adjusted Cox proportional hazard regression models. Over a median follow-up of 8.4 years, 3272 and 17 474 women developed HF and cancer, respectively. HF developed in 235 women prior to cancer. HF was associated with subsequent incident cancer [hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.11-1.48]. Associations were observed for obesity-related cancers (HR 1.24, 95% CI 1.02-1.51), as well as lung and colorectal cancers (HR 1.58, 95% CI 1.09-2.30 and HR 1.52, 95% CI 1.02-2.27, respectively). HF with preserved ejection fraction (HR 1.34, 95% CI 1.06-1.67), but not HF reduced ejection fraction (HR 0.99, 95% CI 0.74-1.34), was associated with total cancer. CONCLUSION: Heart failure was associated with an increase in cancer diagnoses in post-menopausal women. This association was strongest for lung cancer. Further research is needed to appreciate the underlying mechanisms responsible for this association.

Diuretic Dose and NYHA Functional Class Are Independent Predictors of Mortality in Patients With Transthyretin Cardiac Amyloidosis.

BACKGROUND: With increasing diagnoses and available treatment options for transthyretin amyloidosis cardiomyopathy (ATTR-CM), risk stratification of ATTR-CM patients is imperative. OBJECTIVES: We hypothesized that diuretic dose and New York Heart Association (NYHA) functional class are independent predictors of mortality in ATTR-CM and would be incrementally additive to existent risk scores. METHODS: Consecutive ATTR-CM patients referred to a single center were identified. Adjusted Cox proportional hazards models determined the association between diuretic dose (furosemide equivalent in mg/kg) at time of diagnosis and the primary outcome of all-cause mortality. The incremental value of adding diuretic dose and NYHA functional class to existing ATTR-CM risk scores was assessed for discrimination and calibration. RESULTS: 309 patients were identified, with mean age 73.2 ± 9.8 years, 84.1% male, and 66% wild type. Daily mean diuretic dose was 0.6 ± 1.0 mg/kg and significantly associated with all-cause mortality (unadjusted hazard ratio: 2.12 per 1-mg/kg increase, [95% confidence interval: 1.71 to 2.61] and fully adjusted hazard ratio: 1.43 [95% confidence interval: 1.06 to 1.93]). Testing previously published ATTR risk scores, adding diuretic dose as categories (0 mg/kg, >0 to 0.5 mg/kg, >0.5 to 1 mg/kg, and >1 to 2 mg/kg) improved the area under the curve of the Mayo risk score from 0.693 to 0.767 and the UK risk score from 0.711 to 0.787 while preserving calibration. Adding NYHA functional class further improved the area under the curve to 0.798 and 0.816, respectively. CONCLUSIONS: Diuretic dose and NYHA functional class are independent predictors of mortality in ATTR-CM patients and provide incremental value to existing ATTR-CM risk scores.

Pulmonary function tests do not predict mortality in patients undergoing continuous-flow left ventricular assist device implantation.

OBJECTIVES: To investigate the effect of pulmonary function testing on outcomes after continuous flow left ventricular assist device implantation. METHODS: A total of 263 and 239 patients, respectively, had tests of forced expiratory volume in 1 second and diffusing capacity of the lungs for carbon monoxide preoperatively for left ventricular assist device implantations between July 2005 and September 2015. Kaplan-Meier analysis and multivariable Cox regressions were performed to evaluate mortality. Patients were analyzed in a single cohort and across 5 groups. Postoperative intensive care unit and hospital lengths of stay were evaluated with negative binomial regressions. RESULTS: There is no association of forced expiratory volume in 1 second and diffusing capacity of the lungs for carbon monoxide with survival and no difference in mortality at 1 and 3 years between the groups (log rank P = .841 and .713, respectively). Greater values in either parameter were associated with decreased hospital lengths of stay. Only diffusing capacity of the lungs for carbon monoxide was associated with increased intensive care unit length of stay in the group analysis (P = .001). Ventilator times, postoperative pneumonia, reintubation, and tracheostomy rates were similar across the groups. CONCLUSIONS: Forced expiratory volume in 1 second and diffusing capacity of the lungs for carbon monoxide are not associated with operative or long-term mortality in patients undergoing continuous flow left ventricular assist device implantation. These findings suggest that these abnormal pulmonary function tests alone should not preclude mechanical circulatory support candidacy.

Comparison of Multivariate Risk Estimation Models to Predict Prognosis in Patients With Implantable Cardioverter Defibrillators With or Without Cardiac Resynchronization Therapy.

Several multivariate risk score models were developed to predict prognosis of patients with heart failure (HF). We compared 3 models with regard to prediction of mortality in patients with HF who received an implantable defibrillator (ICD) or a cardiac resynchronization therapy defibrillator (CRT-D), as primary prevention of sudden death. The study cohort consisted of 823 patients (ICD = 410; CRT-D = 413). The evaluated models were the Seattle Heart Failure Model (SHFM), the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) score, and an adjusted Charlson Comorbidity Index (aCCI). End point was the performance of the models to predict all-cause mortality at 5 years. This was determined by c-statistics, for both subgroups. Multivariate analysis was used to analyze the relations between the risk score models, their individual components and mortality, and its applicability to the entire population. Cumulative mortality was 4.9% at 1 year and 21.1% at 5 years. Discriminatory power for 5-year mortality was highest for the SHFM (0.73; p <0.001) compared with the MADIT II score and the aCCI for the entire population. SHFM performed better than the MADIT II score for CRT-D group. In the entire population, the SHFM and the aCCI were significant predictors of mortality in multivariate analysis (hazard ratio 1.90, 95% confidence interval 1.49 to 2.43 vs hazard ratio 1.11, 95% confidence interval 1.01 to 1.22). The strongest individual components were age, HF, impaired renal function, and cancer, whereas CRT-D use was no predictor. In conclusion, the SHFM has the best discriminatory power for 5-year mortality in patients with HF with an ICD or CRT-D. The aCCI and MADIT II scores are less powerful but viable alternatives.

An Intervention to Enhance Goals-of-Care Communication Between Heart Failure Patients and Heart Failure Providers.

CONTEXT: Heart failure patients contend with a markedly impaired quality of life, experiencing emotional distress and severe physical discomfort that increases in frequency in the last months of life. Improving communication between patients and providers about goals of care has the potential to improve patient-provider communication and patient outcomes. OBJECTIVES: To determine the effects of a goals-of-care (GoC) intervention compared to usual care on the number of GoC conversations, quality of communication between patients and providers, referrals to palliative care services and completion of advance care directives. METHODS: A two-group randomized study (n = 40/group) compared a GoC intervention to usual care, conducted in an academic heart failure (HF) clinic. The GoC intervention was a previsit patient activation-education, telephone-based intervention delivered by a nurse. The primary outcome of the study was number of GoC conversations between HF patients and HF providers. Secondary outcomes were quality of communication, number of referrals to palliative care, and completion of advance directives. RESULTS: Patients averaged 58.15 ± 11.26 years of age, with mean left ventricular ejection fraction = 30.31 ± 9.72% and Seattle Heart Failure Model scores = 95.1 ± 1.60. There was a significant increase in goals-of-care conversations (58% vs. 2.6%, P < 0.001) and quality of end-of-life communication (P = 0.03) in the GoC group compared to usual care after the intervention. There were no differences between groups on the other outcomes. CONCLUSION: The GoC intervention resulted in more GoC conversations and higher quality communication between HF patients and providers without increased anxiety or depression. Further studies are needed to assess impact on longer term quality of care and patient outcomes.

Improved outcome with repeated intracoronary injection of bone marrow-derived cells within a registry: rationale for the randomized outcome trial REPEAT.

AIMS: Regenerative therapies have evolved as a promising new option in the treatment of post-infarction heart failure. A major limitation of intracoronary application of autologous bone marrow-derived mononuclear cells (BM-MNCs) is that homing of the applied cells is profoundly reduced in patients with post-infarction heart failure compared with patients with acute myocardial infarction. However, early pilot and also randomized controlled trials have demonstrated significant improvements in overall cardiac function. The aim of the present analysis was to quantify a potential mortality risk reduction and reduced hospitalization in order to provide data for a prospective outcome trial. METHODS AND RESULTS: The results of an ongoing single-centre registry including 297 post-infarction heart failure patients suggest that repeated intracoronary application of autologous bone marrow-derived cells is associated with a significant better 2-year survival compared with a single BM-MNC application (2-year survival 93.6 vs. 84.0%, P = 0.03). Likewise, mortality is significantly lower at 2-year follow-up compared with the mortality estimated by the use of the Seattle Heart Failure Model (SHFM) in patients receiving repeated BM-MNC application (observed mortality 6.4%, predicted mortality 16.2%, P = 0.02). Although the trend persisted at 3-year follow-up, the mortality reduction was no longer statistically significant between single and repeated treatment (mortality 21.9 vs. 13.7%, P = 0.06). CONCLUSION: Repeated intracoronary administration of BM-MNC appears to be associated with improved clinical outcome compared with single treatment at 2 years. This registry provides the rationale for the design of the multicentre randomized, controlled, open-label REPEAT trial, which prospectively compares the effects of single vs. repeated intracoronary application of autologous BM-MNC on total and SHFM-predicted mortality in patients with chronic post-infarction heart failure.

Systematic donor selection review process improves cardiac transplant volumes and outcomes.

BACKGROUND: Heart transplant remains the definitive therapy for advanced heart failure patients but is limited by organ availability. We identified a large number of donor hearts from our organ procurement organization (OPO) being exported to other regions. METHODS: We engaged a multidisciplinary team including transplant surgeons, cardiologists, and our OPO colleagues to identify opportunities to improve our center-specific organ utilization rate. We performed a retrospective analysis of donor offers before and after institution of a novel review process. RESULTS: Each donor offer made to our program was reviewed on a monthly basis from July 2013 to June 2014 and compared with the previous year. This review process resulted in a transplant utilization rate of 28% for period 1 versus 49% for period 2 (P = .007). Limiting the analysis to offers from our local OPO changed our utilization rate from 46% to 75% (P = .02). Transplant volume increased from 22 to 35 between the 2 study periods. Thirty-day and 1-year mortality were unchanged over the 2 periods. A total of 58 hearts were refused by our center and transplanted at other centers. During period 1, the 30-day and 1-year survival rates for recipients of those organs were 98% and 90%, respectively, comparable with our historical survival data. CONCLUSIONS: The simple process of systematically reviewing donor turndown events as a group tended to reduce variability, increase confidence in expanded criteria for donors, and resulted in improved donor organ utilization and transplant volumes.

Safety and efficacy of the MitraClip® system for severe mitral regurgitation: a systematic review.

BACKGROUND: The MitraClip® system is a newer percutaneous device that has shown promising results but data on its safety and efficacy in low- and high-surgical risk populations continues to evolve. We performed a systematic review of the published studies reporting the safety and efficacy of MitraClip® implantation for treatment of moderate to severe and severe mitral regurgitation (MR). METHODS: Reviewers independently searched for relevant articles in Medline and abstracted clinical information based on pre-defined criteria and end-points. Patients were classified as low- or high-surgical risk for conventional mitral valve (MV) surgery based on Society of Thoracic Surgeons score, EuroSCORE, or surgeon discretion. Primary safety outcome was 30-day mortality and primary efficacy outcomes were freedom from death, ≥3+ MR, and requirement for MV surgery during follow-up. RESULTS: Immediate and long-term outcomes of 16 studies, including 2980 patients (age 73.7 ± 0.6 years; 63.3% males) receiving the MitraClip®, were analyzed. Acute procedural success rate was 91.4% with a procedural mortality of 0.1%. Mortality at 30 days and long-term (310 days) follow-up was 4.2 and 15.8%, respectively and was significantly higher in the high-risk group (P = 0.003 and 0.019, respectively). Incidence of major procedural adverse outcomes was relatively low with blood transfusion accounting for most events. At follow-up, the number of patients with ≥3+ MR reduced from 96.3% to 14.7% (P < 0.001), and those with NYHA class III/IV reduced from 83.2% to 23.4% (P < 0.001). CONCLUSION: MitraClip® implantation for moderate to severe or severe MR appears to be safe with a very low procedural mortality. There is significant improvement in functional outcomes although long-term mortality is high, especially in high surgical risk patients.

Comparison of the Seattle heart failure model and cardiopulmonary exercise capacity for prediction of death in patients with chronic ischemic heart failure and intracoronary progenitor cell application.

BACKGROUND: Despite many therapeutic advances, the prognosis of patients with chronic heart failure (CHF) remains poor. Therefore, reliable identification of high-risk patients with poor prognosis is of utmost importance. Cardiopulmonary exercise testing (CPET) provides important prognostic information by peak O2 uptake (peak VO2 ), maximal oxygen pulse (O2 Pmax), O2 uptake efficiency slope (OUES), and VE/VCO2 slope (VE/VCO2 ). A different approach for prognostic assessment is the Seattle Heart Failure Model (SHFM), which is based on clinical data and calculates the estimated annual mortality. HYPOTHESIS: Comparison of the prognostic value of the Seattle Heart Failure Score and cardiopulmonary excercis testing in patients with chronic heart failure. METHODS: One hundred fifty-seven patients with ischemic heart failure and recent intracoronary progenitor cell application were analyzed for mortality during a follow-up of 4 years. CPET (peak VO2 , O2 Pmax, OUES, VE/VCO2 ) was performed in all patients at baseline. The SHFM score was calculated for every patient, with data obtained at the time of CPET. RESULTS: During follow-up, 24 patients died (15.2%). Nonsurvivors had significantly worse initial CPET results and a higher SHFM score compared to survivors. Receiver operating characteristics curve analysis of sensitivity and specificity revealed the largest area under the curve value for the SHFM score, followed by VE/VCO2 slope. Kaplan Meier analysis using cutoff points of SHFM and VE/VCO2 slope with highest sensitivity and specificity resulted in significant discrimination of survivors and nonsurvivors. By multivariate analysis, only the SHFM score persisted as independent predictor of mortality in these patients. CONCLUSIONS: These data indicate superior prognostic power of the SHFM score compared to CPET in patients with chronic ischemic heart failure.

Fatigue, inflammation, and projected mortality in heart failure.

BACKGROUND: Fatigue is a prominent and poorly understood symptom of heart failure with reduced ejection fraction (HFrEF). The purpose of this study was to determine whether fatigue correlated with immune biomarkers and prognosis. METHODS/RESULTS: In patients with HFrEF (N = 59) and healthy controls (N = 25), we prospectively measured fatigue (Profile of Mood States), depressive symptoms (Patient Health Questionnaire-8), sleep quality (Pittsburgh Sleep Quality Index), and immune biomarkers (plasma C-reactive protein [CRP], tumor necrosis factor-α [TNFα], and interleukins [IL-6 and IL-10]). Seattle Heart Failure Model (SHFM) mortality risk scores were determined. Patients with HFrEF had significantly greater fatigue and depressive symptoms and poorer sleep quality compared to control subjects. When controlling for depressive symptoms, however, fatigue did not differ significantly between patients with HFrEF and controls. Patients with HFrEF had significantly lower levels of IL-10 compared to controls. Cytokines did not correlate significantly with fatigue, but fatigue was significantly associated with higher SHFM scores. CONCLUSIONS: Depressive symptoms were an important covariate of fatigue in patients with HFrEF. Our study findings were the first to show a positive association between fatigue and the SHFM score, indicating that fatigue was associated with poorer prognosis.

Comparison of observed survival after ventricular assist device placement versus predicted survival without assist device using the Seattle heart failure model.

Determining optimal timing for implant of ventricular assist device (VAD) in end-stage heart failure remains a challenge and may be aided by a risk assessment tool. For a cohort of 80 consecutive VAD implants at a single center, observed 1 year survival post-VAD was compared with the estimated survival had these patients not received a VAD, using the Seattle Heart Failure Model (SHFM). The SHFM was adjusted with a hazard ratio of 1.17 for inotrope use (Cochrane Meta-analysis of phosphodiesterase inhibitors) and a hazard ratio of 2.92 for balloon pump, ventilator, or renal replacement therapy (Comparative Outcome and Clinical Profiles in Transplantation [COCPIT] Model). Values immediately before surgery were used to calculate the SHFM score. Point estimates of 1 year survival were compared using Z scores. Mean age was 53 ± 14 (± standard deviation [SD]) years with mean left ventricular ejection fraction of 17 ± 6%. At the time of VAD implant, 92% were on inotropes, 53% had balloon pump, and 15% were intubated. For the entire cohort, 1 year survival without VAD predicted by the SHFM was 47% versus observed survival after VAD of 60% (p = 0.06). The model was most helpful in patients electively implanted with a left ventricular assist device (LVAD). In this group predicted 1 year survival on medical management was 49% versus an observed survival of 82% after LVAD placement (p < 0.05). The model was least helpful in patients undergoing placement of biventricular assist devices (BiVAD), where the model paradoxically predicted better survival with ongoing medical management. This indicated that the model was unable to forecast outcome in patients with higher severity of illness, for example, in cases warranting BiVAD placement. Observed 1 year survival was better with VAD versus that predicted with medical management. Tools such as the SHFM may aid in determining appropriate timing for VAD by providing an estimated survival with ongoing medical management. The model is best applied to more stable patients being considered for elective VAD implantation.

The vascular marker soluble fms-like tyrosine kinase 1 is associated with disease severity and adverse outcomes in chronic heart failure.

OBJECTIVES: We sought to evaluate placental growth factor (PlGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1) as clinical biomarkers in chronic heart failure (HF). BACKGROUND: Vascular remodeling is a crucial compensatory mechanism in chronic HF. The angiogenic ligand PlGF and its target receptor fms-like tyrosine kinase 1 modulate vascular growth and function, but their relevance in human HF is undefined. METHODS: We measured plasma PlGF and sFlt-1 in 1,403 patients from the Penn Heart Failure Study, a multicenter cohort of chronic systolic HF. Subjects were followed for death, cardiac transplantation, or ventricular assist device placement over a median follow-up of 2 years. RESULTS: The sFlt-1 was independently associated with measures of HF severity, including New York Heart Association functional class (p < 0.01) and B-type natriuretic peptide (p < 0.01). Patients in the 4th quartile of sFlt-1 (>379 pg/ml) had a 6.17-fold increased risk of adverse outcomes (p < 0.01). This association was robust, even after adjustment for the Seattle Failure Model (hazard ratio: 2.54, 95% confidence interval [CI]: 1.76 to 2.27, p < 0.01) and clinical confounders including HF etiology (hazard ratio: 1.67, 95% CI: 1.06 to 2.63, p = 0.03). Combined assessment of sFlt-1 and B-type natriuretic peptide exhibited high predictive accuracy at 1 year (area under the receiver-operator characteristic curve: 0.791, 95% CI: 0.752 to 0.831) that was greater than either marker alone (p < 0.01 and p = 0.03, respectively). In contrast, PlGF was not an independent marker of disease severity or outcomes. CONCLUSIONS: Our findings support a role for sFlt-1 in the biology of human HF. With additional study, circulating sFlt-1 might emerge as a clinically useful biomarker to assess the influence of vascular remodeling on clinical outcomes.

Uric acid level and allopurinol use as risk markers of mortality and morbidity in systolic heart failure.

BACKGROUND: Previous studies have not extensively examined the association of hyperuricemia and adverse outcomes in systolic heart failure (HF) in relation to xanthine oxidase inhibitor therapy. METHODS: The Prospective Randomized Amlodipine Survival Evaluation study included New York Heart Association class IIIB or IV patients with left ventricular ejection fraction <30%. For analysis, the population was divided into uric acid quartiles among nonallopurinol users (2.2-7.1, >7.1-8.6, >8.6-10.4, >10.4 mg/dL) and those using allopurinol. Multivariate Cox regression modeling was performed to identify predictors of mortality. Uric acid quartile and allopurinol groups were referenced to the lowest uric acid quartile. RESULTS: A total of 1,152 patients were included. In general, patients in the allopurinol group and in the highest uric acid quartile had indicators of more severe HF, including worse renal function and greater proportion of New York Heart Association class IV patients, and greater diuretic use. The allopurinol group and highest uric acid quartile had the highest total mortality (41.7 and 42.4 per 100 person-years, respectively) and combined morbidity/mortality (45.6 and 51.0 per 100 person-years, respectively). Allopurinol use and highest uric acid quartile were independently associated with mortality (hazard ratio [HR] 1.65, 95% CI 1.22-2.23, P = .001 and HR 1.35, 95% CI 1.07-1.72, P = .01, respectively) and combined morbidity/mortality (uric acid quartile 4 vs 1: HR 1.32, 95% CI 1.06-1.66, P = .02; allopurinol use: HR 1.48, 95% CI 1.11-1.99, P = .008). CONCLUSION: Elevated uric acid level was independently associated with mortality in patients with severe systolic HF, even when accounting for allopurinol use.

In patients with heart failure elevated soluble TNF-receptor 1 is associated with higher risk of depression.

BACKGROUND: Pro-inflammatory cytokines may contribute to the development and progression of heart failure (HF) and are also implicated in depressive disorders. In this cross-sectional study, we investigated whether systemic inflammation, as assessed by circulating levels of inflammatory cytokines, was associated with comorbid depression in patients with heart failure. METHODS AND RESULTS: Baseline clinical variables, depression status, and inflammatory marker levels were measured in 129 ambulatory HF patients. We hypothesized that pro-inflammatory cytokines, specifically tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6, would be elevated in HF patients with comorbid depression. In unadjusted analyses, levels of soluble TNF-alpha receptor1 (sTNFr1) were significantly higher among depressed (1.6 ng/mL), compared with nondepressed (1.1 ng/mL), HF patients (P = .01). After multivariate adjustment, compared with patients in the lowest quartile of sTNFr1 levels, those in the highest quartile had an adjusted near 5-fold higher risk of depression (OR 4.6, 95% CI 1.2-17.3; P for trend .008). The subgroup of patients on antidepressants but not currently depressed had a trend toward higher levels of sTNFr1, suggesting that antidepressants may not lower cytokine levels even when adequately treating depressive symptoms. IL-1beta and IL-6 levels were not significantly different among depressed versus nondepressed HF patients. CONCLUSIONS: In this cross-sectional analysis, HF patients with comorbid depression, compared with nondepressed HF patients, had higher levels of sTNFr1 and trend toward higher levels of sTNFr1 even when adequately treated for depression.