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The prediction of sudden cardiac death (SCD) in heart failure (HF) remains an unmet need. The aim of our study was to assess the prevalence of SCD over 20 years in HF outpatients managed in a Mediterranean multidisciplinary HF Clinic, and to compare the proportion of SCD (SCD/all-cause death) to the expected proportional occurrence based on the validated Seattle Proportional Risk Model (SPRM) score.This prospective observational registry study included 2,772 HF outpatients admitted between August 2001 and May 2021. Patients were included when the cause of death was known and SPRM score was available.Over the 20-year study period, 1,351 (48.7%) patients died during a median follow-up period of 3.8 years (interquartile range 1.6-7.6). Among these patients, the proportion of SCD out of the total of deaths was 13.6%, while the predicted by SPRM was 39.6%. This lower proportion of SCD was observed independently of left ventricular ejection fraction, ischemic etiology, and the presence of an implantable cardiac defibrillator.In a Mediterranean cohort of HF outpatients, the proportion of SCD was lower than expected based on the SPRM score. Future studies should investigate to what extend epidemiological and guideline-directed medical therapy patterns influence SCD.

Background Prognostic evaluation in heart failure (HF) is important to predict future events and decide timely management. Many HF patients are treated with the use of an implantable cardioverter-defibrillator (ICD). This study aimed to validate a meta-analytically derived prognostic score to predict survival in ICD-HF patients. Methods and Results The HF Meta-score includes 14 independent mortality predictors identified in a meta-analysis, including age, sex, ethnicity, diabetes, chronic obstructive pulmonary disease, peripheral vascular disease, atrial fibrillation, ischemic cardiomyopathy, history of HF admission, New York Heart Association functional class, left ventricular ejection fraction, renal function, QRS duration, secondary prevention indication, and ICD shocks. The HF Meta-score performance was evaluated in comparison with the Seattle Heart Failure Model (SHFM) and the SHOCKED predictors in a cohort of 9860 ambulatory ICD patients from the Ontario provincial database for 2007–2011. During 3-year follow-up, 1816 patients died. The HF Meta-score showed excellent calibration, very good discrimination (c-statistic 0.74) and enhanced risk classification compared with the SHOCKED predictors, with better reclassifying in 19% and 56% of patients for 1- and 3-year survival, respectively. HF Meta-score performance was similar to the SHFM. Conclusions The HF Meta-score is an evidence-based derived model that provides an accurate prognosis assessment in HF patients with ICDs. Its development strategy permits further incorporation of new predictors when evidence becomes available.

Precise risk stratification in heart failure (HF) patients enables clinicians to tailor the intensity of their management. The Seattle Heart Failure Model (SHFM), which uses conventional clinical variables for its prediction, is widely used. We aimed to externally validate SHFM in Japanese HF patients with a recent episode of acute decompensation requiring hospital admission.SHFM was applied to 2470 HF patients registered in the West Tokyo Heart Failure and National Cerebral And Cardiovascular Center Acute Decompensated Heart Failure databases from 2006 to 2016. Discrimination and calibration were assessed with the use of the c-statistic and calibration plots, respectively, in HF patients with reduced ejection fraction (HFrEF;40%) and preserved ejection fraction (HFpEF; ≥40%). In a perfectly calibrated model, the slope and intercept would be 1.0 and 0.0, respectively. The method of intercept recalibration was used to update the model. The registered patients (mean age 74 ± 13 y) were predominantly men (62%). Overall, 572 patients (23.2%) died during a mean follow-up of 2.1 years. Among HFrEF patients, SHFM showed good discrimination (c-statistic = 0.75) but miscalibration, tending to overestimate 1-year survival (slope = 0.78; intercept = -0.22). Among HFpEF patients, SHFM showed modest discrimination (c-statistic = 0.69) and calibration, tending to underestimate 1-year survival (slope = 1.18; intercept = 0.16). Intercept recalibration (replacing the baseline survival function) successfully updated the model for HFrEF (slope = 1.03; intercept = -0.04) but not for HFpEF patients.In Japanese acute HF patients, SHFM showed adequate performance after recalibration among HFrEF patients. Using prediction models to tailor the care for HF patients may improve the allocation of medical resources.

Background The timing of transplant listing after implantation of a left ventricular assist device (LVAD) remains uncertain, given high device complication rates and apparent stability of some LVAD-supported patients. This investigation quantifies the effect of delayed transplant listing and transplantation rates on medium-term survival and LVAD complications. Methods and Results A Markov model was used to simulate the effects of delaying initial transplant listing after LVAD implantation. Modeled parameters were derived from the Standard Transplant Analysis and Research file. When transplant listing was delayed and 5-year results were examined, fewer persons underwent transplantation (53% in base model vs 51% in 180-day-delay model) and the fraction of deaths while waiting increased (17% in base model vs 21% in 180-day delay model). Life expectancy changed minimally from the base model (3.50 y) when initial listing was delayed by 180 days (3.51 y). Conclusions Delaying initial transplant listing increased the likelihood of death while waiting for a transplant and decreased the likelihood of transplantation. In aggregate, life expectancy was unchanged by delays in listing. This study suggests that delaying transplant listing with the expectation of providing additional life expectancy is not likely with current LVAD technology.

Prognostic models, such as the Seattle Heart Failure Model (SHFM), have been developed to predict patient survival. The extent to which they predict medical resource use and costs has not been explored. In this study, we evaluated relationships between baseline SHFM scores and 1-year resource use and costs using data from a clinical trial.We applied generalized linear models to examine the relative impact of a 1-unit increase in SHFM scores on counts of medical resource use and direct medical costs at 1 year of follow-up. Of 2331 randomized patients, 2288 (98%) had a rounded integer SHFM score between -1 and 2, consistent with predicted 1-year survival of 98% and 74%, respectively. At baseline, median age was 59 years, 28% of patients were women, and nearly two-thirds of the cohort had New York Heart Association class II heart failure and one-third had class III heart failure. Higher SHFM scores were associated with more hospitalizations (rate ratio per 1-unit increase, 1.86; P.001), more inpatient days (2.30; P.001), and higher inpatient costs (2.28; P.001), outpatient costs (1.54; P.001), and total medical costs (2.13; P.001).Although developed to predict all-cause mortality, SHFM scores also predict medical resource use and costs.

Introduction The Carillon device was studied in a blinded randomized trial (REDUCE FMR) and demonstrated improvements in regurgitant volume (RV) and LV dimensions at one year compared to a sham control group. It is not clear what are the characteristics of better responders to this therapy, especially if sicker pts will respond. Methods Data from REDUCE FMR (included pts with EF's Results Results are summarized in Table 1.RV responders had lower EF's, similar LVEDV and higher RV's at baseline as compared to non-responders. LVEDV responders had lower EF's, larger LVEDV and more RV than LVEDV non-responders. Pts with afib were more likely to be a responder when the parameter was remodeling, but less likely to be a responder with regards to improvement in MR. Non-ischemics did better using either definition of responders. Continuous variable values are mean ±standard deviation* p Conclusions The Carillon device seems to have a greater impact in pts with worse EF's and more RV at baseline, representing a higher risk population. Although the use of Carillon may be clinically important in pts with lesser degrees of MR (catching them earlier in the disease), greater relative changes may be observed in sicker pt populations.

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.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.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.

The Seattle Heart Failure Model (SHFM) is a multivariable model with proven prognostic value. Cardiopulmonary exercise testing (CPX) and neurohormonal markers (eg, B-type natriuretic peptide [BNP]) are also well accepted assessment techniques in the HF population and have both demonstrated robust prognostic value. The purpose of this investigation was to assess the combined prognostic value of the SHFM and CPX.This study included all 453 patients enrolled in the Multicenter In-Sync Randomized Clinical Evaluation (MIRACLE) trial. Baseline SHFM and CPX were used. Both peak oxygen consumption (VO(2)) and ventilatory efficiency (VE/VCO(2)) were determined. In a univariate Cox proportional model analysis, SHFM and log-transformed peak VE/VCO(2) were stronger predictors of 6-month mortality (both P .001) than log-transformed BNP (P = .013) or peak VO(2) (P = .066). In a multivariable Cox proportional hazards model, neither peak VO(2) nor BNP were independent predictors when added to the SHFM (P .1). Conversely, peak VE/VCO(2) was a strong independent predictor when added to the SHFM, with an increase in the Cox proportional hazards model Wald χ(2) from 22.7 for SHFM alone to 33.8 with inclusion of log-transformed peak VE/VCO(2) (P .0001) and significant changes in the net reclassification improvement and integrated discrimination index (both P .002).These results indicate that the SHFM and peak VE/VCO(2) work synergistically to improve prognostic resolution. Further investigation is needed to continue to optimize multivariable prognostic models in patients with HF, a chronic disease population that continues to suffer from a high adverse event rate despite advances in medical care.

Background Depression impairs health status among patients with coronary disease. The effect of depression on patients with heart failure has been studied to date only in hospitalized patients. Methods and results Prospective cohort study of 113 outpatients with advanced heart failure. At baseline, 19% (n = 21) had major depression or dysthymia, 9% (n = 10) had minor depression, and 72% (n = 82) had no current depression diagnosis. Repeated measures analyses of covariance adjusting for demographic and clinical differences demonstrated that the depression groups differed on observed function (6-minute walk distance [F = 4.8, P = .01]), and self-reported generic (SF-36) and disease-specific (Kansas City Cardiomyopathy Questionnaire) health status. Depression groups also differed in severity of self-reported breathlessness, chest pain, and fatigue. Subject- and spouse-reported role function also differed between the groups. Partial correlation (controlling for the same covariates) between baseline Hamilton Depression Scale scores and these outcomes was highly significant at baseline and follow-up. Conclusions Depression is prospectively associated with poorer health status in patients with advanced heart failure. Physical and role function, symptom severity, and quality of life are all significantly affected.

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)-α, interleukin (IL)-1, and IL-6, would be elevated in HF patients with comorbid depression. In unadjusted analyses, levels of soluble TNF-α 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-1β 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.

Background Patient-centered health status measures are important because they capture the patient's perspective on their heart failure, but it is unclear which of these have independent prognostic significance. Methods and Results A total of 142 consecutive subjects from a specialty heart failure clinic were assessed at baseline with a broad array of clinical, laboratory, and self-report measures including four summary measures of health status. The relationships between these measures and their association with the combined end point of transplantation or death over a mean follow-up of 3 years were examined. In unadjusted analyses, the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score had the strongest association with the combined end point (HR [for each unit score difference] = 0.98 [0.96–0.99], P = .002). In the adjusted Cox proportional hazards model including all 4 summary measures, the Seattle Heart Failure Score, V0 2, systolic blood pressure, and medical comorbidity, only the Standard Gamble utility remained significantly associated with time to the combined end point (HR [for each 0.01 utility score difference] = 0.98 [0.97–0.99], P = .007). Conclusions Our study suggests that summary health status measures are simple and significant indicators of prognosis in advanced heart failure patients. The KCCQ summary score summarizes a wide range of clinical variables from the patient's point of view, whereas the standard gamble utility contains important prognostic information not captured in usual clinical variables.

Hg. Mean left atrial volume index was 49.8617.1 sq cm. After the initial diagnosis with a two year followup, there were no readmissions in 65.3% of patients who were on appropriate diuretic therapy and had regular clinical visits. Frequent readmissions were seen in 34.7% of patients inspite of appropriate diuretic therapy. All-cause mortality rate was 4.3% at two year follow up. Conclusions: In patients with stiff left atrial syndrome, most consistent associated features were increased mean pulmonary capillary wedge pressure with significantly peaked V waves on right heart catheterization and increased left atrial size. Based on established diagnosis, judiciously directed therapeutic strategies with diuretics were shown to prevent hospital readmissions and improve long term clinical outcomes. Inspite of awareness of this unique clinical entity, it is still poorly understood and appropriate therapeutic regimens to stabilize or stem disease progression are still elusive.

A Multimarker Panel Improves Risk Prediction in Chronic Heart Failure Bonnie Ky, Benjamin French, James C. Fang, Nancy K. Sweitzer, Wayne C. Levy, AlanH.B.Wu, LeeR.Goldberg,Mariell Jessup, ThomasP.Cappola; Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA; Cardiovascular Medicine, Case Western University, Cleveland, OH; Cardiovascular Medicine, University of Wisconsin, Madison, WI; Cardiovascular Medicine, University of Washington, Seattle, WA; Department of Laboratory Medicine, University of California at San Francisco, San Francisco, CA

Background: Nitrotyrosine (N-tyr) was initially proposed to be a specific marker of increased oxidative stress related to the generation of peroxynitrite from nitric oxide in vascular endothelial cells and other tissues. Although several non-nitric oxide biosynthetic pathways for N-tyr have also been described, in all cases tyrosine nitration is believed to involve free radical chemistry reactions. Increased plasma N-tyr levels have been previously reported in patients with coronary artery disease. Chronic heart failure (CHF) is known to be associated with increased levels of markers of lipid peroxidation, but plasma levels of N-tyr in CHF have not been previously reported. Methods and Results: We measured plasma N-tyr, soluble vascular cell adhesion molecule (sVCAM) with ELISA, flow-mediated dilation (FMD) in the brachial artery with high resolution ultrasound, and other clinical variables in 40 clinically stable ambulatory subjects with CHF of mixed etiology. N-tyr was significantly increased in CHF subjects when compared with normals (389 588 vs. 20 30 nM). In univariate analyses, N-tyr was significantly associated with etiology of CHF (non-ischemic 463 108 vs. ischemic 38 20 nM), the presence of diabetes mellitus (nondiabetic 489 113 vs. diabetic 44 31 nM), and use of statins (no statin 533 140 vs. statin 194 96 nM). N-tyr was not associated with age, NYHA class, ejection fraction, use of beta-blockers, FMD, or sVCAM. In multivariate analysis only the presence of diabetes mellitus remained significantly associated with N-tyr levels (p 0.01). Conclusions: N-tyr, a proposed marker of oxidative stress, is increased in subjects with CHF, especially those with non-ischemic etiololgy. The strong association of diabetes mellitus with decreased levels of N-tyr is unexpected and suggests that the physiological factors that regulate tyrosine nitration are complex.