Disease Severity In Heart Failure Research Articles

Exhaled Breath Analysis Using Selected Ion Flow Tube Mass Spectrometry and Disease Severity in Heart Failure.

Exhaled breath volatile organic compounds (VOCs) are elevated in heart failure (HF). The ability of VOCs to predict long term cardiovascular mortality and morbidity has not been independently verified. In 55 patients admitted with acute decompensated heart failure (ADHF), we measured exhaled breath acetone and pentane levels upon admission and after 48 h of diuresis. In a separate cohort of 51 cardiac patients undergoing cardiopulmonary exercise testing (CPET), we measured exhaled breath acetone and pentane levels before and at peak exercise. In the ADHF cohort, admission acetone levels correlated with lower left ventricular ejection fraction (LVEF, r = -0.297, p = 0.035). Greater weight loss with diuretic therapy correlated with a greater reduction in both acetone levels (r = -0.398, p = 0.003) and pentane levels (r = -0.309, p = 0.021). In patients with above-median weight loss (≥4.5 kg), patients demonstrated significantly greater percentage reduction in acetone (59% reduction vs. 7% increase, p < 0.001) and pentane (23% reduction vs. 2% reduction, p = 0.008). In the CPET cohort, admission acetone and pentane levels correlated with higher VE/VCO2 (r = 0.39, p = 0.005), (r = 0.035, p = 0.014). However, there were no significant correlations between baseline or peak exercise acetone and pentane levels and peak VO2. In longitudinal follow-up with a median duration of 33 months, patients with elevated exhaled acetone and pentane levels experienced higher composite adverse events of death, ventricular assist device implantation, or orthotopic heart transplantation. In patients admitted with ADHF, higher exhaled breath acetone levels are associated with lower LVEF and poorer outcomes, and greater reductions in exhaled breath acetone and pentane tracked with greater weight loss. Exhaled acetone and pentane may be novel biomarkers in heart failure worthy of future investigation.

Artificial intelligence and heart failure: Astate-of-the-art review.

Heart failure (HF) is a heterogeneous syndrome affecting more than 60 million individuals globally. Despite recent advancements in understanding of the pathophysiology of HF, many issues remain including residual risk despite therapy, understanding the pathophysiology and phenotypes of patients with HF and preserved ejection fraction, and the challenges related to integrating a large amount of disparate information available for risk stratification and management of these patients. Risk prediction algorithms based on artificial intelligence (AI) may have superior predictive ability compared to traditional methods in certain instances. AI algorithms can play a pivotal role in the evolution of HF care by facilitating clinical decision making to overcome various challenges such as allocation of treatment to patients who are at highest risk or are more likely to benefit from therapies, prediction of adverse outcomes, and early identification of patients with subclinical disease or worsening HF. With the ability to integrate and synthesize large amounts of data with multidimensional interactions, AI algorithms can supply information with which physicians can improve their ability to make timely and better decisions. In this review, we provide an overview of the AI algorithms that have been developed for establishing early diagnosis of HF, phenotyping HF with preserved ejection fraction, and stratifying HF disease severity. This review also discusses the challenges in clinical deployment of AI algorithms in HF, and the potential path forward for developing future novel learning-based algorithms to improve HF care.

Cholesterol Content of Very-Low-Density Lipoproteins Is Associated with 1-Year Mortality in Acute Heart Failure Patients.

Considering the relationship between the extent of metabolic derangement and the disease severity in heart failure, we hypothesized that the lipid content of very-low-density lipoprotein (VLDL) may have prognostic value for 1 year mortality in acute heart failure (AHF). Baseline serum levels of VLDL cholesterol (VLDL-C), VLDL triglycerides (VLDL-TG), VLDL phospholipids (VLDL-PL), and VLDL apolipoprotein B (VLDL-apoB) were measured using NMR spectroscopy. We calculated the ratios of the respective VLDL lipids and VLDL apoB (VLDL-C/VLDL-apoB, VLDL-TG/VLDL-apoB, and VLDL-PL/VLDL-apoB), as estimators of the cholesterol, triglyceride, and phospholipid content of VLDL particles and tested their association with mortality. Out of 315 AHF patients, 118 (37.5%) patients died within 1 year after hospitalization for AHF. Univariable Cox regression analyses revealed a significant inverse association of VLDL-C/VLDL-apoB (hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.29–0.64, p < 0.001), VLDL-TG/VLDL-apoB (HR 0.79, 95% CI 0.71–0.88, p < 0.001), and VLDL-PL/VLDL-apoB (HR 0.37, 95% CI 0.25–0.56, p < 0.001) with 1 year mortality. Of the tested parameters, only VLDL-C/VLDL-apoB remained significant after adjustment for age and sex, as well as other clinical and laboratory parameters that showed a significant association with 1 year mortality in the univariable analyses. We conclude that cholesterol content of circulating VLDL (VLDL-C/VLDL-apoB) might be of prognostic value in AHF.

Abstract 11150: Albuminuria in Heart Failure is More Strongly Associated with Markers of Congestion Than Renal Dysfunction

Aims: Albuminuria is common in patients with heart failure (HF) and associated with worse outcomes. It is unknown whether albuminuria only reflects renal dysfunction or whether it is related to the pathophysiology of HF. We therefore aimed to study the clinical characteristics and biomarkers associated with albuminuria in patients with new onset or worsening HF. Methods and Results: In the current analysis, we included 2315 patients from the index cohort of BIOSTAT-CHF who had a spot urinary sample available at baseline, and validated findings in 1431 patients from the independent BIOSTAT-CHF validation cohort.Micro-albuminuria and macro-albuminuria were defined as UACR &gt;30 mg/gCr and &gt;300 mg/gCr, respectively.In the index cohort 242 patients (10%) had macro- and 819 (35.4%) had micro-albuminuria. Patients with any albuminuria were more likely to be hospitalized, had a higher NYHA-class, more clinical signs of congestion and higher concentrations of biomarkers related to congestion, such as bio-ADM, CA-125 and NT pro-BNP. Moreover, they were more likely to have a history of diabetes mellitus (56.6% vs. 27.7% for macro-albuminuria vs. no albuminuria), hypertension and atrial fibrillation (all p&lt;0.001). From multivariable linear regression the strongest predictor for log(UACR) was log NT pro-BNP (standardized B 0.41, 95% CI 0.32 - 0.50, p &lt;0.001). This correlation was similar for all estimated glomerular filtration rates (p for interaction = 0.256). A dendrogram based on hierarchical clustering (Figure) demonstrates that UACR clusters with markers of congestion and HF disease severity and not with markers of renal (dys)function. The validation cohort yielded similar findings. Conclusion: In patients with HF, the presence of albuminuria was more strongly related to markers of congestion than markers of renal dysfunction. These data may suggest a direct relationship between congestion and albuminuria or a common underlying pathophysiological mechanism.

Early- and late anthracycline-induced cardiac dysfunction: echocardiographic characterization and response to heart failure therapy

BackgroundAnthracycline-induced cardiac dysfunction (ACD) is a notorious side effect of anticancer treatment. It has been described as a phenomenon of a continuous progressive decline of cardiac function, eventually leading to dilated cardiomyopathy (DCM). This progressive nature suggests that patients with a delayed ACD diagnosis have greater compromise of cardiac function and more adverse remodeling, with a poor response to heart failure (HF) treatment. This study aimed to delineate the impact of a delayed ACD diagnosis on echocardiographic characteristics and response to HF treatment.Methods and resultsFrom the population of our cardio-oncology outpatient clinic, 92 ACD patients were included in this study (age 51.6 ± 16.2 years, median cumulative anthracycline dose 329 [200–329] mg/m2), and a median follow-up of 25.0 [9.6–37.2] months after ACD diagnosis. Median time to ACD diagnosis for patients diagnosed early (< 1 year) and late (> 1 year) was 4.0 vs. 47.7 months respectively. There were no echocardiographic differences between patients diagnosed early vs. late (LVEF 43.6 ± 4.9% vs. 43.0 ± 6.2% and iEDV 63.6 vs. 62.9 mL/m2). Eighty-three percent of patients presented with mild LV dysfunction and in 79% the LV was not dilated. Patients diagnosed early were more likely to have (partial) recovery of cardiac function upon HF treatment initiation (p = 0.015).ConclusionsIn the setting of a cardio-oncology outpatient clinic, patients with ACD presented with a hypokinetic non-dilated cardiomyopathy, rather than typical DCM. Timing of ACD diagnosis did not impact HF disease severity. However, in patients receiving an early diagnosis, cardiac function was more likely to recover upon HF treatment.

Ventricular arrhythmias not meeting criteria for terminating cardiopulmonary exercise testing stratify prognosis and disease severity in heart failure of preserved, midrange, and reduced ejection fraction.

BackgroundContinued high mortality in heart failure patients indicates the need for additional methods of risk stratification and phenotyping.HypothesisWe hypothesized that ventricular arrhythmias that do not meet test‐termination criteria (non‐terminating ventricular arrhythmias [NTVA]) during cardiopulmonary exercise testing (CPET) may help in phenotyping disease severity and prognosis in heart failure with reduced (HFrEF) and midrange (HFmrEF)/preserved (HFpEF) left ventricular ejection fraction (LVEF).MethodsAbout 319 patients with heart failure (199 HFrEF; 80 HFmrEF; 41 HFpEF) underwent CPET. Tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) were measured by echocardiography. B‐type natriuretic peptide (BNP) at rest and peak exercise was also determined. The patients were tracked for primary (cardiac death) and secondary composite outcomes (all‐cause death, heart transplantation/left ventricular assist device implantation, hospitalization for cardiac reasons).ResultsForty‐seven (15%) of the patients demonstrated NTVA during CPET, regardless of coronary artery disease prevalence. Patients without arrhythmias had a significantly higher LVEF (P < .05), TAPSE/PASP ratio (P < .001), peak oxygen consumption (P < .01), lower resting and peak BNP (P < .001), and the minute ventilation/carbon dioxide production slope (P < .001) compared to those with NTVA. Seventy‐one patients died during the tracking period, 54 for cardiac reasons. NTVA during CPET was a significant predictor of primary and secondary outcomes in the total heart failure cohort (HR: 5.3, 3.7; 95% CI: 3.1‐9.1, 2.4‐5.5; P < .001, respectively), as well as in subgroups categorized according to reduced and middle‐range/preserved LVEF (P < .001).ConclusionExercise‐induced ventricular arrhythmias that do not reach test‐termination criteria are nonetheless indicative of an advanced disease severity phenotype and worse prognosis.

P6327Non-terminating ventricular arrhythmias during exercise testing reflect poorer prognosis and advanced disease severity in heart failure regardless of ejection fraction

Abstract Introduction Electrocardiography is an integral component of cardiopulmonary exercise testing (CPET), a standard of care in patients with heart failure (HF). We hypothetized that ventricular arrhythmias during CPET that do not meet test-termination criteria (NTVA) set forth by current guidelines may help in phenotyping disease severity and prognosis in HF with either reduced (rEF), and mid-range (mrEF)/preserved (pEF) left ventricular (LV) ejection fraction. Methods 319 patients with HF (199 HFrEF; 80 HFmrEF; 41 HFpEF) underwent CPET. Tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) were measured by echocardiography. B-type natriuretic peptide (BNP) at rest and peak exercise were also determined. The patients were tracked for the primary [cardiac death] and secondary composite outcome [all-cause death, heart transplantation/left ventricular assist device implantation, hospitalization for cardiac reasons]. Results 47 (15%) of the patients demonstrated NTVA during CPET, regardless of coronary artery disease prevalence. Patients without arrhythmias had a significantly higher LVEF (p&lt;0.05), TAPSE/PASP ratio (p&lt;0.001), peak oxygen consumption (p&lt;0.01), lower resting and peak BNP (p&lt;0.001) and the minute ventilation/carbon dioxide production slope (p&lt;0.001) compared to those with NTVA. 71 patients died during the tracking period, 54 for cardiac reasons. NTVA during CPX were a significant predictor of primary and secondary outcome in all patients with HF (HR: 5.3, 3.7; 95% CI: 3.1–9.1, 2.4–5.5, p&lt;0.001, respectively) as well as in subgroups categorized according to reduced, middle range and preserved LVEF (p&lt;0.001). Conclusion These results indicate that exercise-induced ventricular arrhythmias not reaching criteria for test termination are nonetheless indicative of an advanced disease severity phenotype and worse prognosis.

P3559Renal sympathetic nerve activity, assessed by renal 123-iodine metaiodobenzylguanidine scintigraphy, reflects disease severity in heart failure with reduced ejection fraction

Abstract Background Sympathetic nerve activity is related to cardio-renal syndrome, which plays a crucial role in deterioration in heart failure with reduced ejection fraction (HFrEF). Previous studies reported that renal denervation was effective in HFrEF patients. Recently, we have demonstrated that renal 123-iodine metaiodobenzylguanidine (MIBG) scintigraphy is useful for assessment of renal sympathetic function in hypertension. However, it is unclear whether renal MIBG would reflect disease severity in HFrEF patients. Methods Twenty-four HFrEF patients and eleven control without heart failure were included in this study. HFrEF patients were performed MIBG and MSNA and hemodynamics inspection using Swan-Ganz's catheter (SGC). HFrEF was defined as echocardiography with EF of 50% or less. MSNA was recorded from the right peroneal nerve to evaluate direct sympathetic nerve activity to the peripheral vascular bed. MSNA was expressed as the number per minute (burst frequency = BF) and the number per 100 heartbeats (burst incidence = BI). Renal MIBG scintigraphy was simultaneously performed with cardiac MIBG scintigraphy. The 20 minutes (early) and 180 minutes (delayed) kidney-to-mediastinum ratio (K/M), early and delayed heart-to-mediastinum ratio (H/M), and washout rate (WR) were measured. Results In the HFrEF group, the EF was significantly lower than control group (EF 34.8±9.51% vs. 63.0±7.43, p&lt;0.01), and MSNA parameters were significantly increased (burst incidence (BI), 57.7±18.7 vs. 37.0±11.3, p&lt;0.01; BF 42.7±14.4 vs. 24.1±8.50, p&lt;0.01). WR of cardiac MIBG was not related to MSNA parameters but negatively related to cardiac output (r=−0.46, p&lt;0.05) and stroke volume (r=−0.61, p&lt;0.01) and delayed H/M negatively correlated with mean pulmonary capillary wedge pressure (r=−0.57, P&lt;0.05). WR of both left and right renal MIBG showed a strong correlation with MSNA (BI; left, r=0.69, p&lt;0.01, right 0.60, p&lt;0.01, BF; left, r=0.64, p&lt;0.01, right, r=0.58, p&lt;0.01) and no significant correlation between renal MIBG and hemodynamics parameters. HFrEF patients were divided into stage B and stage C based on American College of Cardiology/American Heart Association (ACC/AHA) classification (stage B, n=13; stage C, n=11). There was no significant difference between the two groups in cardiac MIBG parameters. Renal WRs in stage C was increased than stage B (Lt renal WR,51.6±10.6 vs. 40.6±6.53, p&lt;0.05; Rt renal WR, 43.9±9.97 vs. 35.1±11.3, p&lt;0.05). Conclusions Cardiac WR negatively correlated with cardiac output and renal WR correlated with MSNA. Renal WRs had a significant difference in the heart failure stage of ACC/AHA classification, but cardiac MIBG parameters did not. These results indicate that renal MIBG might be useful to assess renal sympathetic nerve activity in patients with HFrEF and suggesting that renal SNA might be promising therapeutic target in HFrEF.

Abstract 944: Differential Dna Methylation Co-segregates With the Severity of Heart Failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. As a potential epigenetic biomarker, DNA methylation differs between healthy and diseased hearts. However, its association according to disease severity has not yet been studied. Here, we sought to investigate how DNA methylation (DNAm) differs across HF disease severity, and study the use of a DNMT methyltransferase inhibitor RG108 on DNAm and its effect on heart function. A fixed dose of Isoprenaline (ISO), or saline control (SAL), administered to a hybrid mouse diversity panel (HMDP) consisting of 85 classical and recombinant inbred mouse strains produced a range of cardiac hypertrophy and/or LV dilatation. Left ventricles were harvested and subjected to genome-wide cardiac DNAm profiling by Reduced Representation Bisulfite Sequencing (RRBS). Unsupervised clustering of the top 1% most variable CpG methylation segregated strains to their genetic origin. Disregarding strain-specific methylation differences, differential methylation between ISO and SAL unexpectedly categorised mice into mild and severe disease responders. In the severe-responder strain BTBRT, the pharmacological DNMT methyltransferase inhibitor, RG108, rescued disease from ISO-response, with accompanying evidence of gene expression recovery. This work establishes the range of cardiac differential DNAm correlating according to disease severity. It displays the involvement of DNA methylation-dependent gene expression changes that turns out to be unique, despite different mouse strain backgrounds. This gives further proof of principle that cardiac DNAm changes represent novel biomarkers for disease stratification and consequent targeted therapy.

The Contribution of Living Arrangements, Social Support, and Self-efficacy to Self-management Behaviors Among Individuals With Heart Failure: A Path Analysis.

Living arrangements, social support, and self-efficacy have significant implications for self-management science. Despite the theoretical linkages among the 3 concepts, there is limited empirical evidence about their interplay and the subsequent influence on heart failure (HF) self-management. The aim of this study was to validate components of the Individual and Family Self-management Theory among individuals with HF. This is a secondary analysis of cross-sectional data generated from a sample of 370 individuals with HF. A path analysis was conducted to examine the indirect and direct associations among social environment (living arrangements), social facilitation (social support) and belief (self-efficacy) processes, and self-management behaviors (HF self-care maintenance) while accounting for individual and condition-specific factors (age, sex, race, and HF disease severity). Three contextual factors (living arrangements, age, and HF disease severity) had direct associations with perceived social support and self-efficacy, which in turn were positively associated with HF self-management behaviors. Living alone (β = -.164, P = .001) was associated with lower perceived social support, whereas being an older person (β = .145, P = .004) was associated with better support. Moderate to severe HF status (β = -.145, P = .004) or higher levels of perceived social support (β = .153, P = .003) were associated with self-efficacy. Our results support the Individual and Family Self-management Theory, highlighting the importance of social support and self-efficacy to foster self-management behaviors for individuals with HF. Future research is needed to further explore relationships among living arrangements, perceived and received social support, self-efficacy, and HF self-management.

Antibodies to receptors are associated with biomarkers of inflammation and myocardial damage in heart failure

Naturally occurring antibodies are linked to inflammation, tissue injury and apoptosis, processes also linked to heart failure. Associations between antibodies, inflammation and myocardial damage, have not been elucidated in heart failure. We investigated if 25 antibodies to receptors expressed in the cardiovascular system were associated with troponin-T, biomarkers of inflammation and clinical measures of disease severity, in patients with heart failure. Antibodies in sera from patients (n=191) with ischemic (n=155) or non-ischemic (n=36) heart failure were measured with full-receptor sandwich enzyme-linked immunosorbent assays. All patients underwent coronary angiography with determination of left ventricular ejection fraction (LVEF) and left ventricular end-diastolic pressure (LVEDP). Measured biomarkers included troponin-T, C-reactive protein, erythrocyte sedimentation rate, fibrinogen and neopterin. Stabilin-1-antibodies correlated with troponin-T (β 0.23 p=0.008), soluble endoglin-antibodies with erythrocyte sedimentation rate (β 0.19, p=0.007) and fibrinogen (β 0.28, p<0.001). Platelet-derived growth factor subunit β-antibodies were associated with neopterin (β 0.17, p=0.002). All antibodies were correlated (R 0.26 to 0.91) and formed 4 principal components (PCs). Patients with high CRP and high PC2 had higher NYHA class and patients with high troponin-T and high PC1 had lower LVEDP (interactions, all p<0.05). Antibodies to receptors are correlated and are associated with biomarkers of inflammation and myocardial damage, which further modifies their association with disease severity in heart failure. Their functional activity and immunological function, remain undecided.

Defining Ambulatory Advanced Heart Failure: MedaMACS and Beyond.

Extended survival with LVADs has generated interest in implantation for ambulatory patients with advanced heart failure (HF) prior to dependence on inotropes, though we remain limited in our ability to define and advance indications in this less sick advanced HF population. The MedaMACS and ROADMAP studies have informed prognosis and decision-making for ambulatory patients with advanced HF. Sicker INTERMACS profiles are consistently associated with high risk of death or rescue LVAD. Appropriately selected patients in profile 4 should be considered for LVADs based on their high mortality and poor quality of life. These studies also shed light on discordant perceptions of HF disease severity between patients and their physicians. For ambulatory patients with HF not at imminent risk of death, shared decision-making about LVAD requires measured and individualized consideration of risk and benefit beyond survival. Future studies, including the ongoing REVIVAL study, should provide additional prognostic information in this patient population and should aid patients, caregivers, and physicians as they contemplate complex decisions regarding LVAD therapy.

Blood pressure reactivity to psychological stress is associated with clinical outcomes in patients with heart failure

Cardiovascular (CV) reactivity to psychological stress has been implicated in the development and exacerbation of cardiovascular disease (CVD). Although high CV reactivity traditionally is thought to convey greater risk of CVD, the relationship between reactivity and clinical outcomes is inconsistent and may depend on the patient population under investigation. The present study examined CV reactivity in patients with heart failure (HF) and its potential association with long-term clinical outcomes. One hundred ninety-nine outpatients diagnosed with HF, with ejection fraction ≤40%, underwent an evaluation of blood pressure (BP) and heart rate reactivity to a laboratory-based simulated public-speaking stressor. Cox proportional hazards regression models were used to examine the prospective association between BP and heart rate reactivity on a combined end point of death or CV hospitalization over a 5-year median follow-up period. Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) reactivity, quantified as continuous variables, were inversely related to risk of death or CV hospitalization (Ps < .01) after controlling for established risk factors, including HF disease severity and etiology. In similar models, heart rate reactivity was unrelated to outcome (P = .12). In models with tertiles of reactivity, high SBP reactivity, compared with intermediate SBP reactivity, was associated with lower risk (hazard ratio [HR] = .498, 95% CI .335-.742, P =.001), whereas low SBP reactivity did not differ from intermediate reactivity. For DBP, high reactivity was marginally associated with lower risk compared with intermediate DBP reactivity (HR = .767, 95% CI .515-1.14, P =.193), whereas low DBP reactivity was associated with greater risk (HR = 1.49, 95% CI 1.027-2.155, P =.0359). No relationship of heart rate reactivity to outcome was identified. For HF patients with reduced ejection fraction, a robust increase in BP evoked by a laboratory-based psychological challenge was associated with lower risk for adverse CVD events and may be a novel and unique marker of left ventricular systolic reserve that is accompanied by a more favorable long-term prognosis.

Effectiveness and Safety of Digoxin Among Contemporary Adults With Incident Systolic Heart Failure

Clinical guidelines recommend digoxin for patients with symptomatic systolic heart failure (HF) receiving optimal medical therapy, but this recommendation is based on limited, older trial data. We evaluated the effectiveness and safety of digoxin in a contemporary cohort of patients with incident systolic HF. We identified adults with incident systolic HF between 2006 and 2008 within Kaiser Permanente Northern California who had no prior digoxin use. We used multivariable extended Cox regression to examine the association between new digoxin use and risks of death and HF hospitalization, controlling for medical history, laboratory results, medications, HF disease severity, and the propensity for digoxin use. We also conducted analyses stratified by sex and concurrent β-blocker use. Among 2891 newly diagnosed patients with systolic HF, 529 (18%) received digoxin. During a median 2.5 years of follow-up, incident digoxin use was associated with higher rates of death (14.2 versus 11.3 per 100 person-years) and HF hospitalization (28.2 versus 24.4 per 100 person-years). In multivariable analysis, incident digoxin use was associated with higher mortality (hazard ratio, 1.72; 95% confidence interval, 1.25-2.36) but no significant difference in the risk of HF hospitalization (hazard ratio, 1.05; 95% confidence interval, 0.82-1.34). Results were similar in analyses stratified by sex and β-blocker use. Digoxin use in patients with incident systolic HF was independently associated with a higher risk of death but no difference in HF hospitalization.

Self-care and renal dysfunction in patients with chronic heart failure

Purpose: It has been shown that impaired renal function is a strong predictor of mortality in patients with chronic heart failure (HF). From a behavioural perspective, self-care has been assumed to be a crucial factor in chronic HF patients to maintain health. However, no prior studies have examined whether self-care is associated with improved renal function. Therefore, we prospectively examined the association between HF self-care and renal function at 1-year follow-up. Methods: In total, 482 chronic HF outpatients (mean age 66.2±9.5 years, 74% men) were recruited from 4 teaching hospitals in the Netherlands. All patients completed the shortened 9-item version of the European Heart Failure Self-care Behaviour scale to assess HF self-care and consultation behaviour at baseline and at 1-year follow-up. Renal function was measured at both consecutive time points using glomerular filtration rates of creatinine. Other HF-related pathophysiological markers of HF disease progression were also measured at both time points including heart pump function (left ventricular ejection fraction and brain natriuretic peptide), liver function, and anemia. Results: By means of linear mixed modeling using maximum likelihood estimation, better HF self-care and consultation behaviour were associated with lower glomerular filtration rates over time (p=.009 and p=.06, respectively), indicating worse renal functioning even after controlling for age, sex, disease severity using New York Heart Association functional class, and standard risk factors. In contrast, regular physical activity was associated with better renal function (p=.03). HF self-care was not associated with other pathophysiological markers of disease severity. Conclusions: HF self-care was associated with renal dysfunction over time. While there was no association between self-care and other pathophysiological markers of HF disease severity, physical activity activity was associated with improved renal function over time. Patient's awareness of their renal dysfunction might prompt better self-care, but the true nature of the link between self-care and clinical outcomes in patients with chronic HF warrants more attention in future research.

Angiopoietin-2 in Adults with Congenital Heart Disease and Heart Failure

BackgroundChronic heart failure is an important cause for morbidity and mortality in adults with congenital heart disease (ACHD). While NT-proBNP is an established biomarker for heart failure of non-congenital origin, its application in ACHD has limitations. The angiogenic factors Angiopoietin-1 and -2 (Ang-1, Ang-2), vascular endothelial growth factor (VEGF), and soluble receptor tyrosine kinase of the Tie family (sTie2) correlate with disease severity in heart failure of non-congenital origin. Their role in ACHD has not been studied.MethodsIn 91 patients Ang-2 and NT-proBNP were measured and related to New York Heart Association class, systemic ventricular function and parameters of cardiopulmonary exercise testing. Ang-1, VEGF, and sTie2 were also measured.ResultsAng-2 correlates with NYHA class and ventricular dysfunction comparable to NT-proBNP. Further, Ang-2 showed a good correlation with parameters of cardiopulmonary exercise testing. Both, Ang-2 and NT-proBNP identified patients with severely limited cardiopulmonary exercise capacity. Additionally, Ang-2 is elevated in patients with a single ventricle physiology in contrast to NT-proBNP. VEGF, Ang-1, and sTie2 were not correlated with any clinical parameter.ConclusionThe performance of Ang-2 as a biomarker for heart failure in ACHD is comparable to NT-proBNP. Its significant elevation in patients with single ventricle physiology indicates potential in this patient group and warrants further studies.

Elevated extracellular HSP70 (HSPA1A) level as an independent prognostic marker of mortality in patients with heart failure

Predicting the survival of a patient with heart failure (HF) is a complex problem in clinical practice. Our previous study reported that extracellular HSP70 (HSPA1A) correlates with markers of heart function and disease severity in HF, but the predictive value of HSP70 is unclear. The goal of this study was to analyze extracellular HSP70 as predictive marker of mortality in HF. One hundred ninety-five patients with systolic heart failure were enrolled and followed up for 60months. By the end of follow-up, 85 patients were alive (survivors) and 110 died (nonsurvivors). HSP70 (measured by ELISA in the serum) was elevated in nonsurvivors, compared with survivors (0.39 [0.27-0.59] vs. 0.30 [0.24-0.43] ng/ml, respectively, p = 0.0101). In Kaplan-Meier survival analysis higher HSP70 levels above median were associated with a significantly increased mortality. In multivariable survival models, we show that HSP70 level above the median is an age-, sex-, body mass index-, creatinine-, and NT-proBNP-independent predictor of 5-year mortality in HF. Extracellular HSP70 could prove useful for estimating survival in patients with HF.

Clinical Adoption of Prognostic Biomarkers: The Case for Heart Failure

The recent explosion of scientific knowledge and technological progress has led to the discovery of a large array of circulating molecules commonly referred to as biomarkers. Biomarkers in heart failure (HF) research have been used to provide pathophysiologic insights, aid in establishing the diagnosis, refine prognosis, guide management, and target treatment. However, beyond diagnostic applications of natriuretic peptides, there are currently few widely recognized applications for biomarkers in HF. This represents a remarkable discordance considering the number of molecules that have been shown to correlate with outcomes, refine risk prediction, or track disease severity in HF in the past decade. In this article, we use a broad framework proposed for cardiovascular risk markers to summarize the current state of biomarker development for patients with HF. We use this framework to identify the challenges of biomarker adoption for risk prediction, disease management, and treatment selection for HF and suggest considerations for future research.

HMGB1 is an independent predictor of death and heart transplantation in heart failure

High-Mobility-Group Box 1 (HMGB1) has been established as an important mediator of myocardial inflammation and associated with progression of heart failure (HF). The aim of this study was to analyze the prognostic value of systemic HMGB1 levels in HF patients with ischemic and non-ischemic cardiomyopathy. We conducted an analysis (median follow-up time 2.5 years) of HMGB1 plasma concentration in 154 patients with systolic HF and correlated the results with disease severity and prognosis. HMGB1 in HF patients with severe symptoms (NYHA III/IV; 5.35 ng/ml; interquartile range (IQR) = 3.48-8.42 ng/ml) was significantly elevated compared with that in patients with mild symptoms (NYHA I/II; 3.37 ng/ml, IQR = 2.31-5.22 ng/ml, p < 0.0001) and with controls (3.25 ng/ml, IQR = 3.04-3.67 ng/ml, p < 0.0001). HMGB1 levels correlated with other markers of heart failure indicating an association of HMGB1 with disease severity in HF. In a univariate cox regression model for the combined endpoint of death and heart transplantation, HMGB1 proved to be a predictor at cut-off values based on HMGB1 terciles of either 3.4 or 6.1 ng/ml (p = 0.001 and p < 0.0001, respectively). In a multivariate cox regression model, which included NT-proBNP, creatinine, age, NYHA class, white blood cell count, anemia, and age, HMGB1 remained an independent predictor of the combined endpoint (hazard ratio (HR) = 2.48, 95% confidence interval (CI) = 1.06-5.83, p = 0.037 and HR = 2.48, 95% CI = 1.31-4.71, p = 0.005, respectively). Our findings demonstrate that HMGB1 plasma concentration is elevated in HF and correlates with disease severity and that is an independent predictor of the combined endpoint death and heart transplantation in HF patients.

Is Vitamin D Deficiency Associated With Heart Failure? A Review of Current Evidence

An estimated 1 billion people worldwide have deficient or insufficient levels of vitamin D. Even more alarming is the association of vitamin D deficiency with many types of diseases, particularly heart failure (HF). Hypovitaminosis D has been observed to be highly prevalent in the HF community with rates varying from approximately 80% to 95%. Higher rates of deficiency have been linked to winter months, in patients with protracted decompensated HF, darker skin pigmentation, and higher New York Heart Association (NYHA) classes. In fact, some data suggest vitamin D deficiency may even be an independent predictor of mortality in patients with HF. Traditionally obtained through UV exposure and activated in the liver and then the kidneys, vitamin D is classified as a vitamin but functions as a steroid hormone. The hormone acts through the vitamin D receptor (VDR), which is expressed in vascular smooth muscle cells, renal juxtaglomerular cells, and most interestingly, cardiac myocytes. Studies have shown that the association between vitamin D deficiency and HF often manifests in the structural components of cardiac myocytes and/or through alterations of the neurohormonal cascade. In addition, vitamin D may also act rapidly through intracellular nongenomic receptors that alter cardiac contractility. Unfortunately, prospective vitamin D supplementation trials show mixed results. In rat models, successful correction of deficiency was associated with reductions in ventricular hypertrophy. In humans, however, echocardiographic dimensions did not change significantly. These results bring into questions whether vitamin D is a risk factor for HF, a marker of HF disease severity, or has a true pathologic role. This article provides a thorough review of vitamin D deficiency etiology, prevalence, and possible pathophysiologic role in HF. Furthermore, we carefully review prospective trials on vitamin D therapy in HF. We believe more trials on vitamin D therapy in HF need to be conducted before any conclusions can be drawn.