Marker Of Heart Failure Severity Research Articles

Circulating beta-hydroxybutyrate levels in advanced heart failure with reduced ejection fraction: Determinants and prognostic impact.

Patients with heart failure (HF) display metabolic alterations, including heightened ketogenesis, resulting in increased beta-hydroxybutyrate (β-OHB) formation. We aimed to investigate the determinants and prognostic impact of circulating β-OHB levels in patients with advanced HF and reduced ejection fraction (HFrEF). A total of 867 patients with advanced HFrEF (age 57 ± 11 years, 83% male, 45% diabetic, 60% New York Heart Association class III), underwent clinical and echocardiographic examination, circulating metabolite assessment, and right heart catheterization (n = 383). The median β-OHB level was 64 (interquartile range [IQR] 33-161) μmol/L (normal 0-74 μmol/L). β-OHB levels correlated with increased markers of lipolysis (free fatty acids [FFA]), higher natriuretic peptides, worse pulmonary haemodynamics, and lower humoral regulators of ketogenesis (insulin/glucagon ratio). During a median follow-up of 1126 (IQR 410-1781) days, there were 512 composite events, including 324 deaths, 81 left ventricular assist device implantations and 107 urgent cardiac transplantations. In univariable Cox regression, increased β-OHB levels (T3 vs. T1: hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.13-1.72, p = 0.002) and elevated FFA levels (T3 vs. T1: HR 1.39, 95% CI 1.09-1.79, p = 0.008) were both predictors of a worse prognosis. In multivariable Cox analysis evaluating the simultaneous associations of FFA and β-OHB levels with outcomes, only FFA levels remained significantly associated with adverse outcomes. In patients with advanced HFrEF, increased plasma β-OHB correlate with FFA levels, worse right ventricular function, greater neurohormonal activation and other markers of HF severity. The association between plasma β-OHB and adverse outcomes is eliminated after accounting for FFA levels, suggesting that increased β-OHB is a consequence reflecting heightened lipolytic state, rather than a cause of worsening HF.

Correlation between energy loss index and B-type natriuretic peptide: a vector flow mapping study.

Vector Flow Mapping (VFM) and Energy Loss (EL) evaluation are emerging echocardiographic techniques that offer detailed insights into cardiac function. This study aimed to explore the relationship between EL parameters and B-type natriuretic peptide (BNP) levels, a well-established marker of heart failure severity. Our study prospectively enrolled 62 patients experiencing shortness of breath and suspected heart failure, who underwent echocardiography and had BNP levels measured between January 2018 and August 2020. Patients were stratified based on BNP levels, and their clinical and echocardiographic characteristics were evaluated. Univariate and multivariate regression analyses were performed to assess the correlation between BNP levels and various echocardiographic variables, including VFM parameters. Patients were stratified into two groups based on their BNP levels: BNP < 200pg/ml (n = 53) and BNP ≥ 200pg/ml (n = 9). Patients with BNP ≥ 200pg/ml presented significantly different clinical and echocardiographic characteristics, such as older age, larger left ventricular mass and volume indices, higher pulmonary artery systolic pressure, higher E/e' ratio, and larger EL parameters. Multivariate regression analysis demonstrated the E/e' ratio and ELA (EL during Atrial contraction phase/A wave ratio as significant determinants of logBNP. Receiver operating characteristic curve analysis showed ELA/A > 36.0J/m2 as a significant predictor of high BNP with 89% sensitivity and 85% specificity. ELA/A demonstrated an incremental diagnostic value over elevated left atrial pressure for predicting high BNP (C statistic = 0.98 vs 0.74, P = 0.006). This study provides novel insights into the potential utility of EL parameters as auxiliary indicators of cardiac load, thereby enhancing our understanding of heart failure.

N-Terminal Pro-B-Type Natriuretic Peptide as a Marker of Severity of Heart Failure in Children with Congenital Heart Diseases.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been used as a tool for diagnosis, severity assessment and prognostication of congestive heart failure (CHF) in adults, with specific cut off values for diagnosis and denoting points of intervention. However, there is scarcity of paediatric literature regarding role of NT-proBNP as a marker of heart failure severity and prognostication. So, this study was done to assess the utility of NT-proBNP as a marker of severity of heart failure in children with congenital heart diseases. Single centre, prospective observational study. Children (1month to 5years), with congenital heart disease, admitted in the paediatric wards with varying severity of CHF were enrolled. Heart failure severity grading was done according to Laer modification of Ross Classification at the time of presentation to hospital and children were classified as having no/grade I CHF (score: 0-2); mild/grade II CHF (score 3-6); moderate/grade III CHF (score 7-9) or severe/grade IV CHF (score 10-12). NT-proBNP levels were measured within 24h of admission. Eighty children with congenital heart disease were enrolled in this study. As per modified Ross Classification, 11 had grade I/No heart failure (13.7%), 32 children had grade II/mild heart failure (40%), 36 had grade III/moderate heart failure (45%) and only 1 had grade IV/severe heart failure (1.25%). The median NT-proBNP levels (IQR) in the above mentioned grades of heart failure were found to be 321.11 (211.1-411.78pg/ml), 750.62 (474.62-995.2pg/ml), 4159.61 (1440.59-11,857pg/ml) and 11,320.34pg/ml, respectively. Seven children (8.75%) expired. Median NT-proBNP value in seven children who died was significantly higher than those who survived [median (IQR): 11,681.01pg/ml (10,092.72-14,754pg/ml) vs 839.4pg/ml (456.67-3288.09pg/ml), p value < 0.001]. NT-proBNP level of 520.2pg/ml predicted grade II (mild heart failure) or more severe grades of heart failure with Sensitivity, Specificity, Negative Predictive Value and Positive Predictive Value of 83%, 91%, 57.1% and 98%, respectively. NT-proBNP levels increase progressively with increasing severity of CHF and can be used as a marker of severity of heart failure in children with congenital heart disease presenting with CHF.

Ventricular tachycardia predicts all-cause mortality and non-sudden cardiac death in non-ischaemic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): The DCM-VT study was partially supported by an investigator-initiated grant (IIS-310) from Biosense Webster (a Johnson &amp; Johnson company). The DANISH study was supported by unrestricted grants from Medtronic, St. Jude Medical, TrygFonden, and the Danish Heart Foundation. Background Endstage heart failure, ventricular tachycardia (VT) and sudden cardiac death (SCD) are sequels of non-ischaemic cardiomyopathies (NICM). Implantable cardioverter defibrillators (ICDs) can terminate VT and prevent SCD but mortality benefit has been limited in recent trials suggesting that VT may also be associated with non-sudden cardiovascular death (NSCVD). Purpose To assess the effect of VT on all-cause mortality and NSCVD in NICM patients with ICDs. Methods Two multicenter cohorts of NICM patients were merged for analysis: (1) patients randomized to ICD in the DANISH trial, which included patients with NICM, LVEF ≤35% and no prior VT and (2) the DCM-VT study cohort, which included consecutive NICM patients with any LVEF referred for ablation of sustained VT. Predictors for the primary composite outcome of all-cause death and heart transplant (death/HTx) and for the secondary outcome of NSCVD were assessed. In addition, propensity score matching was performed using the parameters age, gender, LVEF and eGFR. Finally, survival following VT occurrence was compared between DANISH and DCM-VT patients. Results A total of 828 patients (556 DANISH, 272 DCM-VT) were followed for a median of 3.9 years (2.1 – 5.8). DANISH patients had a median LVEF of 25% (20 – 30) and DCM-VT patients 35% (27 – 43). A total of 148 patients (DANISH 16.4%, DCM-VT 21.0%) experienced death/HTx and NSCVD occurred in 78 patients (7.7%, 12.9%, respectively). In multivariable analysis history of VT at inclusion was a significant predictor of the primary outcome with an adjusted hazard ratio (HRa) of 3.81 (95% CI 2.33 - 6.24) as were age [HRa 1.02 per year (1.01 - 1.04)], LVEF [HRa 0.96 per 1% increase (0.94 - 0.98)] and reduced eGFR [HRa 1.71 (1.15 – 2.53 )]. History of VT predicted NSCVD with an HRa of 7.54 (3.97 - 14.33). After matching, history of VT still predicted death/HTx [HR 4.12 (2.48 - 6.82)] and NSCVD [HR 6.92 (3.30 - 14.52)]. Risk of death/HTx, as well as NSCVD, for DANISH patients was similar to DCM-VT patients after they experienced their first VT event [HRa 0.90 (0.48 - 1.69) and HRa 1.07 (0.56 - 2.06) resp.]. Conclusions VT occurrence appears to be an important predictor of non-sudden CV death as well as all-cause death in NICM patients independent of other markers of heart failure severity. VT may be a marker of progressive disease and remodelling that could be incorporated into risk-stratification to help predict deterioration and need for HTx.

Clinical predictors of hyponatremia in patients with heart failure according to severity of chronic kidney disease

Chronic kidney disease (CKD) has been associated with adverse clinical outcomes. Hyponatremia, amarker of illness severity and poor prognosis, is commonly exhibited in patients with CKD. This cross-sectional study included patients hospitalized due to heart failure (HF). We used stepwise logistic regression to investigate the independent association of cardiovascular drugs, markers of HF severity, and baseline clinical characteristics with hyponatremia in three subgroups; normal renal function, mild-to-moderate CKD, and severe CKD. Of the 1232patients, 38.6% were hyponatremic. Patients with severe CKD, compared to those with normal renal function and mild-to-moderate CKD, were more likely to be hyponatremic (47.1%, 34.4% and 36.6%, respectively; p ≤ 0.0001). Alcohol consumption, female sex, n-terminal pro-brain natriuretic peptide (NT-proBNP), hydrochlorothiazide (HCT), and mineralocorticoid receptor antagonist (MRA) use, or angiotensinII receptorI blocker (ARB) non-use were associated with hyponatremia in patients with normal renal function (p ≤ 0.03 in all cases). Current smoking, diabetes mellitus, NT-proBNP, loop diuretic dose, and MRA use were predictors in mild-to-moderate CKD (p ≤ 0.04 in all cases). ARB use, loop diuretic dose, and HCT use were predictors in severe CKD (p ≤ 0.03 in all cases). Non-use of dihydropyridine calcium channel blocker (CCB) was an independent predictor of hyponatremia in all CKD stages (p ≤ 0.04 in all cases). Apart from afirm favorable effect of CCBs, cardiovascular therapy should be carefully tailored to avoid hyponatremia in patients with cardiorenal syndrome.

Health-Related Quality of Life and Mortality in Heart Failure: The Global Congestive Heart Failure Study of 23 000 Patients From 40 Countries.

Poor health-related quality of life (HRQL) is common in heart failure (HF), but there are few data on HRQL in HF and the association between HRQL and mortality outside Western countries. We used the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) to record HRQL in 23 291 patients with HF from 40 countries in 8 different world regions in the G-CHF study (Global Congestive Heart Failure). We compared standardized KCCQ-12 summary scores (adjusted for age, sex, and markers of HF severity) among regions (scores range from 0 to 100, with higher score indicating better HRQL). We used multivariable Cox regression with adjustment for 15 variables to assess the association between KCCQ-12 summary scores and the composite of all-cause death, HF hospitalization, and each component over a median follow-up of 1.6 years. The mean age of participants was 65 years; 61% were men; 40% had New York Heart Association class III or IV symptoms; and 46% had left ventricular ejection fraction ≥40%. Average HRQL differed between regions (lowest in Africa [mean± SE, 39.5±0.3], highest in Western Europe [62.5±0.4]). There were 4460 (19%) deaths, 3885 (17%) HF hospitalizations, and 6949 (30%) instances of either event. Lower KCCQ-12 summary score was associated with higher risk of all outcomes; the adjusted hazard ratio (HR) for each 10-unit KCCQ-12 summary score decrement was 1.18 (95% CI, 1.17-1.20) for death. Although this association was observed in all regions, it was less marked in South Asia, South America, and Africa (weakest association in South Asia: HR, 1.08 [95% CI, 1.03-1.14]; strongest association in Eastern Europe: HR, 1.31 [95% CI, 1.21-1.42]; interaction P<0.0001). Lower HRQL predicted death in patients with New York Heart Association class I or II and III or IV symptoms (HR, 1.17 [95% CI, 1.14-1.19] and HR, 1.14 [95% CI, 1.12-1.17]; interaction P=0.13) and was a stronger predictor for the composite outcome in New York Heart Association class I or II versus class III or IV (HR 1.15 [95% CI, 1.13-1.17] versus 1.09 [95% CI, [1.07-1.11]; interaction P<0.0001). HR for death was greater in ejection fraction ≥40 versus <40% (HR, 1.23 [95% CI, 1.20-1.26] and HR, 1.15 [95% CI, 1.13-1.17]; interaction P<0.0001). HRQL is a strong and independent predictor of all-cause death and HF hospitalization across all geographic regions, in mildly and severe symptomatic HF, and among patients with preserved and reduced ejection fraction. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03078166.

The value of spot urinary creatinine as a marker of muscle wasting in patients with new-onset or worsening heart failure.

BackgroundMuscle wasting and unintentional weight loss (cachexia) have been associated with worse outcomes in heart failure (HF), but timely identification of these adverse phenomena is difficult. Spot urinary creatinine may be an easily accessible marker to assess muscle loss and cachexia. This study investigated the association of urinary creatinine with body composition changes and outcomes in patients with new‐onset or worsening HF (WHF).MethodsIn BIOSTAT‐CHF, baseline spot urinary creatinine measurements were available in 2315 patients with new‐onset or WHF in an international cohort (index cohort) and a validation cohort of 1431 similar patients from Scotland.ResultsMedian spot urinary creatinine concentrations were 5.2 [2.7–9.6] mmol/L in the index cohort. Median age was 69 ± 12 years and 73% were men. Lower spot urinary creatinine was associated with older age, lower height and weight, worse renal function, more severe HF, and a higher risk of >5% weight loss from baseline to 9 months (odds ratio = 1.23, 95% CI = 1.09–1.39 per log decrease; P = 0.001). Spot urinary creatinine was associated with Evans criteria of cachexia (OR = 1.26 per log decrease, 95% CI = 1.04–1.49; P = 0.016) and clustered with markers of heart failure severity in hierarchical cluster analyses. Lower urinary creatinine was associated with poorer exercise capacity and quality of life (both P < 0.001) and predicted a higher rate for all‐cause mortality [hazard ratio (HR) = 1.27, 95% CI = 1.17–1.38 per log decrease; P < 0.001] and the combined endpoints HF hospitalization or all‐cause mortality (HR = 1.23, 95% CI = 1.15–1.31 per log decrease; P < 0.001). Significance was lost after addition of the BIOSTAT risk model. Analyses of the validation cohort yielded similar findings.ConclusionsLower spot urinary creatinine is associated with smaller body dimensions, renal dysfunction, and more severe HF in patients with new‐onset/WHF. Additionally, lower spot urinary creatinine is associated with an increased risk of weight loss and a poorer exercise capacity/quality of life. Urinary creatinine could therefore be a novel, easily obtainable marker to assess (risk of) muscle wasting in HF patients.

Microbiota-Derived Metabolite Trimethylamine N-Oxide Protects Mitochondrial Energy Metabolism and Cardiac Functionality in a Rat Model of Right Ventricle Heart Failure.

Aim: Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite synthesized in host organisms from specific food constituents, such as choline, carnitine and betaine. During the last decade, elevated TMAO levels have been proposed as biomarkers to estimate the risk of cardiometabolic diseases. However, there is still no consensus about the role of TMAO in the pathogenesis of cardiovascular disease since regular consumption of TMAO-rich seafood (i.e., a Mediterranean diet) is considered to be beneficial for the primary prevention of cardiovascular events. Therefore, the aim of this study was to investigate the effects of long-term TMAO administration on mitochondrial energy metabolism in an experimental model of right ventricle heart failure.Methods: TMAO was administered to rats at a dose of 120 mg/kg in their drinking water for 10 weeks. Then, a single subcutaneous injection of monocrotaline (MCT) (60 mg/kg) was administered to induce right ventricular dysfunction, and treatment with TMAO was continued (experimental groups: Control; TMAO; MCT; TMAO+MCT). After 4 weeks, right ventricle functionality was assessed by echocardiography, mitochondrial function and heart failure-related gene and protein expression was determined.Results: Compared to the control treatment, the administration of TMAO (120 mg/kg) for 14 weeks increased the TMAO concentration in cardiac tissues up to 14 times. MCT treatment led to impaired mitochondrial function and decreased right ventricular functional parameters. Although TMAO treatment itself decreased mitochondrial fatty acid oxidation-dependent respiration, no effect on cardiac functionality was observed. Long-term TMAO administration prevented MCT-impaired mitochondrial energy metabolism by preserving fatty acid oxidation and subsequently decreasing pyruvate metabolism. In the experimental model of right ventricle heart failure, the impact of TMAO on energy metabolism resulted in a tendency to restore right ventricular function, as indicated by echocardiographic parameters and normalized organ-to-body weight indexes. Similarly, the expression of a marker of heart failure severity, brain natriuretic peptide, was substantially increased in the MCT group but tended to be restored to control levels in the TMAO+MCT group.Conclusion: Elevated TMAO levels preserve mitochondrial energy metabolism and cardiac functionality in an experimental model of right ventricular heart failure, suggesting that under specific conditions TMAO promotes metabolic preconditioning-like effects.

Revisiting heart failure assessment based on objective measures in NYHA functional classes I and II

ObjectiveNew York Heart Association (NYHA) functional class plays a central role in heart failure (HF) assessment but might be unreliable in mild presentations. We compared objective measures of HF functional...

Heart Failure Optimize Clinic: Improving Quality of Care In Heart Failure Patients In An Academic Medical Center

Background While heart failure (HF) is a leading cause of mortality and readmissions, only a small percentage of patients are optimized on guideline-directed medical therapy (GDMT). We developed a multidisciplinary HF clinic to optimize medications, provide education and resources and screen for medical co-morbidities in HF patients. Methods A multidisciplinary clinic composed of Advanced Practice Providers (APPs), pharmacist, nutritionists and nurses was developed and targeted patients with a 30-day HF readmission, ≥ 2 HF-related hospitalizations in last 12 months or new HF diagnosis. The OPTIMIZE clinic consisted of a total of 6 visits approximately two weeks apart seeing an APP at each visit along with pharmacy and nutrition evaluation. Echocardiographic, 6-minute walk, and health related quality of life (EQ5D) outcomes were measured at baseline and at the end of the 12 weeks. Results A total of 62 patients with heart failure with reduced ejection fraction (HFrEF) completed OPTIMIZE clinic over an average of 11.6 weeks. Patients were primarily white (62.3%) males (56.5%) with an average age of 59.1 (±15.3) years. HF etiology was primarily non-ischemic (65%) and patients had typical cardiac comorbidities - hypertension 54%, hyperlipidemia 33%, diabetes 23%, sleep apnea 15%, and chronic kidney disease 24%. Completion of OPTIMIZE clinic resulted in significant improvements in 6-minute walk distance, left ventricular ejection fraction (LVEF), and patient reported quality of life measures as assessed by the EQ5D along with significant reductions in brain natriuretic peptide (BNP) and left ventricular internal diameter in diastole (LVIDd) (Figure 1a). We also saw improved utilization of GDMT with completion of the OPTIMIZE clinic (Figure 1b). During the course of the clinic, only 7 (11%) patients were admitted for CHF exacerbation and 44 referrals were made to various other cardiology or internal medicine subspecialities, the most common being sleep clinic (14 referrals). A total of 13 (21%) patients had enough improvement in LVEF on GDMT as a result of this clinic that they no longer met criteria for implantable cardioverter defibrillator implantation. Conclusion Successful implementation of a multidisciplinary HF optimization clinic can help improve GDMT utilization, HF education, comorbidity recognition, and markers of HF severity. An OPTIMIZE clinic model can be considered in other centers as a way to increase GDMT optimization and improve clinical and functional markers of HF.

P429The efficacy of electrical cardioversion of long-standing persistent or permanent atrial fibrillation in cardiac resynchronization therapy recipients

Abstract Funding Acknowledgements Institute of Cardiology statutory grant (grant no.: 2.30/VII/13) Background Atrial fibrillation (AF) and heart failure (HF) often co-exist and influence each other. The presence of AF is often regarded as a marker of HF severity. Moreover, AF in cardiac resynchronization therapy (CRT) recipients hinders the CRT effectiveness in HF treatment by the reduction of the percentage of biventricular paced beats (BiVp%). Sinus rhythm (SR) restoration makes CRT more effective in HF treatment which may protect AF recurrence. Purpose To establish the effectiveness of electrical external cardioversion (EEC) in CRT patients with long-standing persistent AF or permanent, pre-treated with amiodarone. Methods The population of the study comprised of the Pilot-CRAfT study participants (NCT01850277), that is patients with CRT, long-standing persistent or considered as permanent AF and BiVp ≤ 95% who were randomly assigned to the "rhythm control" or the "rate control" strategy. The inclusion criteria included an AF paroxysm lasting at least 6 months. Both treatment arms received amiodarone beginning with the loading dose. Subsequently, patients assigned to the rhythm control strategy underwent electrical cardioversion. Rate control strategy included pharmacotherapy and atrioventricular node ablation, as needed. The follow up visit was performed 3 months after the enrolment visit. The EEC effectiveness, an AF recurrence within the 3 month period, BiVp% changes, the EEC parameters and the EEC related complications were analysed. Results Out of 48 participants enrolled in the Pilot-CRAfT study, 25 patients were assigned to the rhythm control arm. The mean age of the rhythm control arm patients was 69,5 years , the mean left ventricular ejection fraction was 30,6% , the mean left atrium diameter was 53 mm and the median duration of persistent AF was 16 months. SR was obtained in 12 out of 20 (60%) patients who underwent the EEC . On the 3 month visit 8 patients remained in SR (40%). In patients with an AF paroxysm lasting less than 1 year the success rate was 100% vs 50% in the AF lasting 1 year at least (p = 0,11 ). After 3 months, SR remained in 100% vs 25% of patients, respectively (p =0,015.). The effectiveness of anterior-posterior EEC electrodes placement was 20% and it was 71% for the anterior-lateral patch location . The EEC resulted in significant BiVp% rise - also in the whole intention-to-treat (ITT) group: 88,58% before the EEC vs 96,68% after the EEC (p = 0,002). No severe adverse events of the EEC were observed. Conclusions The electrical cardioversion of persistent atrial fibrillation lasting more than 6 months in patients with severe HF and treated with CRT is characterised by modest success rate, even after the amiodarone pre-treatment. However, the ECC ensures significant rise in BiVp% close to 97%, even in the whole EEC group based on the ITT principle. The AF paroxysm duration &amp;lt;1 year and the anterior-posterior patch placement may ensure better EEC efficacy in this group of patients.

The Role of Cardiac T-Cadherin in the Indicating Heart Failure Severity of Patients with Non-Ischemic Dilated Cardiomyopathy.

Background and objectives: T-cadherin (T-cad) is one of the adiponectin receptors abundantly expressed in the heart and blood vessels. Experimental studies show that T-cad sequesters adiponectin in cardiovascular tissues and is critical for adiponectin-mediated cardio-protection. However, there are no data connecting cardiac T-cad levels with human chronic heart failure (HF). The aim of this study was to assess whether myocardial T-cad concentration is associated with chronic HF severity and whether the T-cad levels in human heart tissue might predict outcomes in patients with non-ischemic dilated cardiomyopathy (NI-DCM). Materials and Methods: 29 patients with chronic NI-DCM and advanced HF were enrolled. Patients underwent regular laboratory investigations, echocardiography, coronary angiography, and right heart catheterization. TNF-α and IL6 in serum were detected by enzyme-linked immunosorbent assay (ELISA). Additionally, endomyocardial biopsies were obtained, and the levels of T-cad were assessed by ELISA and CD3, CD45Ro, CD68, and CD4- immunohistochemically. Mean pulmonary capillary wedge pressure (PCWP) was used as a marker of HF severity, subdividing patients into two groups: mean PCWP > 19 mmHg vs. mean PCWP < 19 mmHg. Patients were followed-up for 5 years. The study outcome was composite: left ventricular assist device implantation, heart transplantation, or death from cardiovascular causes. Results: T-cad shows an inverse correlation with the mean PCWP (rho = −0.397, p = 0.037). There is a tendency towards a lower T-cad concentration in patients with more severe HF, as indicated by the mean PCWP > 19 mmHg compared to those with mean PCWP ≤ 19 mmHg (p = 0.058). Cardiac T-cad levels correlate negatively with myocardial CD3 cell count (rho = −0.423, p = 0.028). Conclusions: Univariate Cox regression analysis did not prove T-cad to be an outcome predictor (HR = 1, p = 0.349). However, decreased T-cad levels in human myocardium can be an additional indicator of HF severity. T-cad in human myocardium has an anti-inflammatory role. More studies are needed to extend the role of T-cad in the outcome prediction of patients with NI-DCM.

The omega-3 index in patients with heart failure: A prospective cohort study

BackgroundEpidemiologic studies on the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in heart failure are scarce, while one large intervention trial demonstrated a modest benefit. MethodsThis is a secondary analysis from the Interdisciplinary Network Heart Failure (INH) program. Patients hospitalized for systolic heart failure were enrolled and followed for 36 months. At baseline, whole blood samples from 899 patients were analyzed for fatty acid composition using a standardized analytical procedure (HS-Omega-3 Index®, O3-I). Associations of the O3-I with markers of heart failure severity, clinical characteristics, biomarkers, and mortality were analyzed. ResultsThe mean O3-I was 3.7 ± 1.0%. Patient mean age was 68 ± 12 years (72% male, 43% in New York Heart Association (NYHA) class III or IV, mean LVEF 30 ± 8%). During follow-up 258 patients (28.7%) died. After adjustment for potential confounders, the O3-I showed weak associations with uncured malignancy, end-systolic diameter of the left atrium, left ventricular end-diastolic and end-systolic diameters, and blood lipids and other laboratory parameters (all p < 0.05), but not with NYHA class, left ventricular ejection fraction, and the underlying cause of heart failure. The O3-I did not predict the 3-year mortality risk. ConclusionsOur results show a marked depletion of omega-3 fatty acids in patients hospitalized for decompensated heart failure (suggested target range 8–11%). Although the O3-I was associated with a panel of established risk indicators in heart failure, it did not predict mortality risk. Clinical Trial Registrationwww.controlled-trials.com; ISRCTN23325295

Association between atrial fibrillation and patient-important outcomes in heart failure patients with implantable cardioverter-defibrillators: a systematic review and meta-analysis.

To assess the association between atrial fibrillation (AF) and all-cause mortality and implantable cardioverter-defibrillators (ICDs) therapies in heart failure (HF) patients with reduced ejection fraction and an ICD implanted. A systematic MEDLINE search performed from inception through November 2016, supplemented by hand searching of reference lists, identified 62 eligible studies (227998 patients) reporting on the association between AF and outcomes in HF patients; 36 studies included data on all-cause mortality, 30 on appropriate, and 17 on inappropriate ICD interventions. Hazard ratio, risk ratio, or odds ratio estimates were used based on data availability. Effect estimates were synthesized under a random-effects model. Implantable cardioverter-defibrillator-implanted HF patients with a history of AF had a 42% {combined effect estimate (cEE) 1.42 [95% confidence interval (CI) 1.28-1.57]} higher risk of all-cause mortality compared with patients with no AF history. Furthermore, AF patients had a higher risk of appropriate [cEE 1.44 (95% CI 1.27-1.64)] and inappropriate ICD interventions [cEE 2.05 (95% CI 1.75-2.44)]. Atrial fibrillation history is statistically significantly associated with adverse major clinical outcomes in ICD-implanted HF patients. Patients with AF have a higher risk of all-cause mortality, appropriate, and inappropriate ICD interventions compared with patients with no AF history. Whether AF may have an independent deleterious effect on HF prognosis or may simply be a marker of HF severity should be further investigated.

Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF.

To date, clinical evidence of microvascular dysfunction in patients with heart failure (HF) with preserved ejection fraction (HFpEF) has been limited. We aimed to investigate the prevalence of coronary microvascular dysfunction (CMD) and its association with systemic endothelial dysfunction, HF severity, and myocardial dysfunction in a well defined, multi-centre HFpEF population. This prospective multinational multi-centre observational study enrolled patients fulfilling strict criteria for HFpEF according to current guidelines. Those with known unrevascularized macrovascular coronary artery disease (CAD) were excluded. Coronary flow reserve (CFR) was measured with adenosine stress transthoracic Doppler echocardiography. Systemic endothelial function [reactive hyperaemia index (RHI)] was measured by peripheral arterial tonometry. Among 202 patients with HFpEF, 151 [75% (95% confidence interval 69-81%)] had CMD (defined as CFR <2.5). Patients with CMD had a higher prevalence of current or prior smoking (70% vs. 43%; P = 0.0006) and atrial fibrillation (58% vs. 25%; P = 0.004) compared with those without CMD. Worse CFR was associated with higher urinary albumin-to-creatinine ratio (UACR) and NTproBNP, and lower RHI, tricuspid annular plane systolic excursion, and right ventricular (RV) free wall strain after adjustment for age, sex, body mass index, atrial fibrillation, diabetes, revascularized CAD, smoking, left ventricular mass, and study site (P < 0.05 for all associations). PROMIS-HFpEF is the first prospective multi-centre, multinational study to demonstrate a high prevalence of CMD in HFpEF in the absence of unrevascularized macrovascular CAD, and to show its association with systemic endothelial dysfunction (RHI, UACR) as well as markers of HF severity (NTproBNP and RV dysfunction). Microvascular dysfunction may be a promising therapeutic target in HFpEF.

Anemia and Iron Deficiency in Heart Failure: Current Concepts and Emerging Therapies.

Anemia and iron deficiency are important and common comorbidities that often coexist in patients with heart failure. Both conditions, together or independently, are associated with poor clinical status and worse outcomes. Whether anemia and iron deficiency are just markers of heart failure severity or whether they mediate heart failure progression and outcomes and therefore should be treated is not entirely clear. Treatment of anemia in patients with heart failure with erythropoiesis-stimulating agents has been evaluated intensively during the past several years. Unfortunately, these agents did not improve outcomes but were associated with a higher risk of adverse events. Iron deficiency in patients with heart failure can be absolute, when total body iron is decreased, or functional, when total body iron is normal or increased but is inadequate to meet the needs of target tissues because of sequestration in the storage pool. Whereas iron replacement is appropriate in patients with anemia resulting from absolute iron deficiency, it has been unclear whether and how absolute or functional iron deficiency should be treated in nonanemic patients with heart failure. Recently, small studies found that administration of intravenous iron in patients with heart failure and absolute or functional iron deficiency with or without anemia improves symptoms and exercise capacity, but long-term outcomes and safety data are not yet available. In this review, we discuss the causes and pathogenesis of and treatment options for anemia and iron deficiency in patients with heart failure.

Metabolic and Cardiac Adaptation to Chronic Pharmacologic Blockade of Facilitative Glucose Transport in Murine Dilated Cardiomyopathy and Myocardial Ischemia

GLUT transgenic and knockout mice have provided valuable insight into the role of facilitative glucose transporters (GLUTs) in cardiovascular and metabolic disease, but compensatory physiological changes can hinder interpretation of these models. To determine whether adaptations occur in response to GLUT inhibition in the failing adult heart, we chronically treated TG9 mice, a transgenic model of dilated cardiomyopathy and heart failure, with the GLUT inhibitor ritonavir. Glucose tolerance was significantly improved with chronic treatment and correlated with decreased adipose tissue retinol binding protein 4 (RBP4) and resistin. A modest improvement in lifespan was associated with decreased cardiomyocyte brain natriuretic peptide (BNP) expression, a marker of heart failure severity. GLUT1 and −12 protein expression was significantly increased in left ventricular (LV) myocardium in ritonavir-treated animals. Supporting a switch from fatty acid to glucose utilization in these tissues, fatty acid transporter CD36 and fatty acid transcriptional regulator peroxisome proliferator-activated receptor α (PPARα) mRNA were also decreased in LV and soleus muscle. Chronic ritonavir also increased cardiac output and dV/dt-d in C57Bl/6 mice following ischemia-reperfusion injury. Taken together, these data demonstrate compensatory metabolic adaptation in response to chronic GLUT blockade as a means to evade deleterious changes in the failing heart.

Absolute iron deficiency without anaemia in patients with chronic systolic heart failure is associated with poorer functional capacity

Functional status is one of the main concerns in the management of heart failure (HF). Recently, the FAIR-HF and CONFIRM-HF trials showed that correcting anaemia using intravenous iron supplementation improved functional variables in patients with absolute or relative iron deficiency. Relative iron deficiency is supposed to be a marker of HF severity, as ferritin concentration increases with advanced stages of HF, but little is known about the impact of absolute iron deficiency (AID). To study the impact of AID on functional variables and survival in patients with chronic systolic HF. One hundred and thirty-eight non-anaemic patients with chronic systolic HF were included retrospectively. Patients were divided into two groups according to iron status: the AID group, defined by a ferritin concentration<100μg/L and the non-AID group, defined by a ferritin concentration≥100μg/L. Functional, morphological and biological variables were collected, and survival was assessed. Patients in the AID group had a poorer 6-minute walking test (342 vs. 387m; P=0.03) and poorer peak exercise oxygen consumption (13.8 vs. 16.0mL/min/kg; P=0.01). By multivariable analysis, ferritin<100μg/L was associated with impaired capacity of effort, assessed by peak exercise oxygen consumption. By multivariable analysis, there was no difference in total mortality between groups, with a mean follow-up of 5.1±1.1 years. The poorer functional evaluations in iron-deficient patients previously reported are not caused by the merging of two different populations (i.e. patients with absolute or relative iron deficiency). Our study has confirmed that non-anaemic HF patients with AID have poorer peak oxygen consumption. However, AID has no impact on the survival of these patients.

Cheyne-stokes respiration during wakefulness in patients with chronic heart failure.

Cheyne-Stokes respiration (CSR) during sleep has been studied extensively in patients with chronic heart failure (CHF). Prevalence and prognostic significance of CSR during wakefulness in CHF, however, are largely unknown. CSR during wakefulness with an apnea-hypopnea cut-off ≥5/h and moderate to severe CSR with an apnea-hypopnea cutoff ≥15/h were analyzed using polysomnographic recordings in 267 patients with stable CHF with reduced left ventricular (LV) ejection fraction at our institution. Primary endpoint during follow-up was heart transplant-free survival. Fifty of 267 patients (19%) had CSR during wakefulness and 73 of 267 patients (27%) had CSR during sleep. CSR during wakefulness was associated with advanced age, atrial fibrillation, decreased LV ejection fraction, increased LV end-diastolic diameter, brain natriuretic peptide, New York Heart Failure class, and CSR during sleep. During 43months mean follow-up, 67 patients (25%) died and 4 patients (1%) underwent heart transplantation. Multivariate Cox analysis identified age, male gender, chronic kidney disease, and LV ejection fraction as predictors of reduced transplant-free survival. CSR during wakefulness with an apnea-hypopnea cutoff ≥5/h as well as moderate to severe CSR while awake using an apnea-hypopnea cutoff ≥15/h did not predict reduced transplant-free survival independently from confounding factors. CSR during wakefulness appears to be a marker of heart failure severity.

Serum free thiols in chronic heart failure

Oxidative stress is a key element of the pathophysiology of heart failure (HF). As free thiols are readily oxidized by reactive oxygen and sulfur species, their circulating level may directly reflect the systemic redox status. This study addresses the role of serum free thiols in chronic HF, which is of particular interest as free thiols are amenable to therapeutic modulation and thus are a potential target for therapy.Free thiols were measured in serum of 101 previously characterized stable chronic HF patients (93% male, age 63.7±10.0y, left ventricular ejection fraction 34.6±8.2%), adjusted for total serum protein, and subsequently analysed for associations with clinical and outcome parameters.The mean serum free thiol concentration was 3.6±0.5μM/g protein. Patients with above-average levels were younger, had better renal function, lower levels of NT-proBNP and PTH, and higher levels of cholesterol. Furthermore, above-average levels were associated with favourable disease outcome, i.e. a decreased rehospitalisation rate and increased patient survival (HR 0.27 (95% CI 0.11⿿0.62), P=0.002) independent of associated clinical parameters, age and PTH. After adjustment for cholesterol or established prognostic factors in HF, eGFR and NT-proBNP the association was no longer significant, suggesting involvement of these variables in a common pathophysiological pathway.This exploratory study demonstrates favourable associations of serum free thiols with markers of HF severity and prognosis as well as disease outcome, which should be further investigated in larger prospective studies. Restoring redox status by therapeutic modulation of free thiols may be a promising strategy to improve disease outcome in CHF.