Clinical Severity Of Heart Failure Research Articles

Recurrences of atrial fibrillation in patients with heart failure without reduced ejection fraction: a role for CA125

Abstract Background Atrial fibrillation (AF) and heart failure (HF) without reduced ejection fraction often occur together, and their combination is associated with increased morbidity and mortality compared with each disorder alone. Sinus rhythm maintenance seems to be beneficial but challenging in these patients. Purpose We studied the possible value of CA125 to predict recurrences in patients with persistent AF and HF without reduced ejection fraction who underwent electrical cardioversion (ECV). Methods We designed a prospective cohort study by consecutively including all the patients who underwent ECV in our hospital with symptomatic persistent non-valvular AF and a concomitant diagnosis of HF without reduced ejection fraction. We excluded patients with clinical instability or ejection fraction <40%. We defined HF as the presence of diastolic dysfunction in echo (left atrium indexed volume >34 ml/m2 or e/e' >8) or ejection fraction between 40 and 50%. We followed-up them during 6 months for detecting AF recurrences with an ECG-Holter 3 months after ECV and an ECG at 6th month. We considered a recurrence as any AF documentation in ECG or ECG-Holter after the ECV. A peripheral blood sample was extracted just before ECV and CA125 was determined. Kaplan-Meyer analysis was used to study the possible relationship between CA125 plasmatic levels, dichotomized according to the median value, and AF recurrence. Results We included 95 patients with a medium age of 64±9 years old. Of them, 31 (32.6%) were women, 14 (14.7%) had diabetes and 56 (58.9%) hypertension. The medium ejection fraction was 58.14±10.27% and the median CA125 was 10.98±8.97 U/ml. We detected 54 (57.4%) recurrences in 6 months. In patients with AF recurrences, CA125 values were higher than in patients who maintained sinus rhythm (19.28±29.11 U/ml vs. 14.98±17.02 U/ml). CA125 was significantly related with AF recurrences (log-rank 5.37; p=0.021). Conclusions In our sample of patients with persistent AF and HF without reduced ejection fraction, CA125 plasmatic levels are related with AF recurrences after ECV. CA125 has been associated with the clinical severity of HF and the symptoms and signs of fluid congestion. This probably means more ventricular and atrial myocardial damage that might predispose to AF. Sinus rhythm maintenance is specially challenging in patients with HF so those with higher levels of CA125 probably need a closer surveillance and a more aggressive rhythm control. Funding Acknowledgement Type of funding sources: None.

CA125 Predicts Right Heart Hemodynamic and Function and Identifies Distinct Congestion Phenotypes: Guidance for Therapy

<h3>Purpose</h3> Elevated carbohydrate antigen 125 (CA125) correlates with serosal effusions and has previously been thought to be associated with the clinical severity of heart failure (HF) and fluid congestion. We assessed CA125 as a predictor of hemodynamics and investigated the additive prognostic benefit of B-type natriuretic peptide (BNP). <h3>Methods</h3> Between 2015-2019, 235 patients hospitalized for HF were prospectively assessed for CA125 and BNP serum levels simultaneously with echocardiography and right heart study. <h3>Results</h3> CA125 correlated positively with intracardiac pressures and inversely with cardiac index (CI). The strongest correlation was for right atrial pressure (RAP) (ρ = 0.82, p<0.001). CA125 >42 U/mL had a sensitivity of 95.8% and specificity of 95.3% for the prediction of RAP ≥11 mmHg. The predictive accuracy of CA125 vs BNP was superior for RAP (AUC 0.99 vs 0.84, p<0.001) and right ventricular (RV) pressure (AUC 0.99 vs 0.82, p<0.001), but BNP was better for the prediction of pulmonary capillary wedge pressure (AUC 0.95 vs 0.82, p<0.001) and CI (AUC 0.92 vs 0.84, p=0.03). Elevated CA125 was independently associated with increased right heart pressures, while BNP with left-sided filling pressures and lower CI (p<0.05). Combining CA125 and BNP values delineated 4 distinct HF congestion phenotypes (Figure): high CA125-high BNP - reduced ejection fraction (HFrEF) with RV dysfunction; low CA125-high BNP - HFrEF with preserved RV function; and high CA125-low BNP and low CA125-low BNP - preserved EF, with and without RV dysfunction, respectively. <h3>Conclusion</h3> CA125 predicts and quantifies right heart function and hemodynamic. CA125-BNP congestion phenotypes can be used as a guidance for diagnosis (improved diagnosis of HFpEF and delineation of congestion status) and therapy (LVAD candidate selection and individualized drug therapies and titration).

Impact of Major Surgical Procedures on Quality of Life of Patients with Advanced Heart Failure

Purpose Advanced Heart Failure (A-HF) is a clinical condition which interferes with patient identity and perception. Psychological reactions depend on the nature and severity of patient disease, personality and environmental factors. Our goal was to evaluate quality of life of outpatients with left ventricular assist device (LVAD), heart transplantation (HT) and optimal medical treatment (OMT) for heart failure (HF). We additionally analyzed two cohorts of patients resulting different in terms of objective disease severity, to assess eventual perceived quality of life differences. Methods We included all consecutive adult patients presenting at our outpatient clinic for routine follow-up between January and September 2019. Including criteria were: being subjected to right heart catheterization (RHC), presence of LVAD for at least 2 months, HT for at least 2 months. Clinical severity of HF has been stratified using RHC and 6-minute walk test. Psychological parameters were measured by Kellner Symptom Questionnaire, Brief-Illness Perception Questionnaire, and WHO Quality of Life -BREF. Results Overall population consisted of 179 patients (HT=90, LVAD=15, and OMT-HF =74). OMT-HF patients were stratified into advanced and non-advanced (A-HF/NA-HF). A-HF patients walked significant less meters (p 3 (p=0.89), walked meters (p=0.32), CI (p=0.82). In psychological well-being comparison between OMT, LVAD and HT, patients who underwent advanced surgical therapy showed better results in terms of anxiety (p=0.014), depression (p=0.003), anger (p=0.04) and illness perception (p Conclusion Patients undergoing a major surgical procedure, such as LVAD implantation or Heart Transplantation, showed overall better psychological parameters than patients with chronic heart failure treated with medical therapy.

The Association between the Clinical Severity of Heart Failure and Docosahexaenoic Acid Accumulation in Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is a common genetic disease with diverse morphology, symptoms, and prognosis. Hypertrophied myocardium metabolism has not been explored in detail. We assessed the association between myocardium lipid metabolism and clinical severity of heart failure (HF) in HCM using imaging mass spectrometry (IMS). Methods and Results: We studied 16 endomyocardial biopsy (EMB) specimens from patients with HCM. Analysis was conducted using desorption electrospray ionization IMS. The Samples were assigned into two cohorts according to the period of heart biopsy (cohort 1, n=9 and cohort 2, n=7). In each cohort, samples were divided into two groups according to the clinical severity of HF in HCM: clinically severe and clinically mild groups. Signals showing a significant difference between the two groups were analyzed by volcano plot. In cohort 1, the volcano plot identified four signals; the intensity in the clinically severe group was more than twice that of the mild group. Out of the four signals, docosahexaenoic acid (DHA) showed significant differences in intensity between the two groups in cohort 2 (10575.8±2750.3 vs. 19839.3±4803.2, p=0.025). Conclusion: The intensity of DHA was significantly higher in EMB samples from the clinically severe HCM group than in those from the mild group. Funding Information: This study received funding from the Ministry of Education, Science, Sports and Culture of Japan, Grants-in-Aid for Scientific Research (Grant Number 18K08065 [YM]). Declaration of Interests: The authors have no conflicts of interest to disclose. Ethics Approval Statement: All the patients provided informed consent. The institutional review board of Hamamatsu University School of Medicine approved all aspects of this study (application number 17-261). The study was conducted in accordance with the regulations of Declaration of Helsinki.

Association of fractalkine with functional severity of heart failure and impact on clopidogrel efficacy in patients with ischemic heart disease

IntroductionPatients with heart failure (HF) display elevated levels of soluble fractalkine, a chemokine involved in inflammation processes, atherosclerosis and platelet activation. Further, fractalkine has been associated with reduced pharmacodynamic (PD) responsiveness to clopidogrel. The aim of this study was to investigate the association of fractalkine with the severity of HF and its impact on platelet activation and clopidogrel response in patients with coronary artery disease (CAD) with and without HF. Materials and methodsThis prospective PD study included 116 stable CAD patients on DAPT with aspirin and clopidogrel. Subjects were classified in two groups: patients with HF and reduced (<40%) left ventricular ejection fraction (HFrEF group, n = 56) and patients without HF (no HF group, n = 60). Clinical severity of HF was graded according to NYHA classification. Platelet function assays included vasodilator-stimulated phosphoprotein assay, multiple electrode aggregometry and light transmittance aggregometry. Fractalkine and P-selectin concentrations were determined by ELISA. ResultsFractalkine levels progressively increased with the severity of the disease in the HFrEF group (NYHA I: 471.2 ± 52.4 pg/ml, NYHA II: 500.5 ± 38.4 pg/ml, NYHA III: 638.9 ± 54.3 pg/ml, p for linear trend 0.023). Numerically higher concentrations of fractalkine were observed in the HFrEF group compared to the no HF group with borderline significance (p = 0.052). No significant differences in clopidogrel-induced platelet inhibition according to fractalkine values were observed in any of the groups. ConclusionsFractalkine levels were increased in patients with HFrEF and positively associated with the functional severity of the disease. No evident impact of fractalkine on clopidogrel PD efficacy was found.

CA125 Independently Predicts Right Atrial Pressure in Advanced Heart Failure Patients

Carbohydrate antigen 125 (CA125), a marker for ovarian cancer, is thought to be associated with the clinical severity of heart failure (HF) and fluid congestion. Mesothelial cells in the pericardium, pleura, peritoneum and M¨ullerian epithelium produce CA125 presumably in response to mechanical (congestion) stress. With the growing use of left ventricular assist device (LVAD) for advanced HF, assessment of right ventricular (RV) function and hemodynamics is of major interest. We aimed to assess CA125 as a predictor of right heart function and hemodynamics. All 164 patients hospitalized for advanced HF in 2015-2019 were prospectively assessed for CA125 and B-type natriuretic peptide (BNP) levels combined with echocardiography and right heart study. Patients were stratified into 4 groups: high BNP-high CA125 (HB-HC), high BNP-low CA125 (HB-LC), low BNP-high CA125 (LB-HC), and low BNP-low CA125 (LB-LC). High CA125 (>35 IU/ml) significantly predicted high BNP (>400 pg/ml) (95% CI 1.01-1.02, p<0.001). High CA125 accurately predicted an elevated right atrial (RA) pressure irrespective of BNP level (even when the later was low; LB, Figure). Conversely, low CA125 predicted a low RA pressure, even when BNP was high (HB). RV function, assessed by echocardiography, was significantly severely reduced for the HB-HC group (29%) vs the LB-HC (17%), HB-LC (9%), and LB-LC (4%) groups (p<0.001). In an unadjusted analysis, each unit elevation of CA125 was associated with a significant 9% higher odds-ratio (OR) for RA pressure>10mmHg (95% CI 1.06-1.13, p<0.001). After adjustment for gender, hemoglobin and comorbidities, BNP was not significantly associated with RA>10mmHg, whereas CA125 continued to be independently associated with a 9% higher OR for RA>10mmHg, per unit of change (95% CI 1.05-1.15, p<0.001). CA125 independently predicts RA pressure and RV function in advanced HF patients. CA125 is a promising marker for risk stratification of patients being evaluated for LVAD implantation.

Influence of Left Atrial Appendage Amputation on Natriuretic Peptides-A Randomized Controlled Trial.

Closure or amputation of the left atrial appendage (LAA) is a common therapy for atrial fibrillation (AF). As the LAA is a hormone-producing organ, however, amputation is still somewhat controversial. We examined patients after surgical AF therapy with or without LAA amputation to determine the influence of LAA amputation on pro-atrial natriuretic peptide (proANP) and B-type natriuretic peptide (BNP) plasma levels and on clinical severity of heart failure. Twenty-one consecutive patients were prospectively randomized to either undergo LAA amputation (n = 10) or no LAA amputation (n = 11) between 05/2015 and 10/2015. All patients underwent coronary and/or valve surgery and concomitant AF surgery with either cryoablation (n = 3) or radio frequency ablation (n = 17). ProANP and BNP levels were measured preoperatively and until 800 days postoperatively. Baseline proANP values were comparable between the groups (without LAA amputation: 4.2 ± 2.1 nmol/L, with LAA amputation: 5.6 ± 3.6 nmol/L). Postoperatively, proANP levels rose markedly in both groups. Even after LAA amputation, proANP levels remained elevated for 7 days postoperatively but fell to baseline levels at day 31 and remained on baseline level at 800 days postoperatively. ProANP levels in the LAA amputation group (5.8-9.7 nmol/L) were not significantly lower than in the group without LAA amputation (9.2-14.1 nmol/L; p = 0.357). BNP levels also rose after surgery in both groups until day 7. At 800 days after surgery, BNP levels were back at baseline levels in both groups. Clinical follow-up at 2 years postoperatively showed no difference in heart failure symptoms or need for heart failure medication between the groups. In contrast to commonly held beliefs about the endocrine and reservoir functions of the LAA, there seems to be no clinically relevant detrimental effect of LAA amputation on natriuretic peptide levels and severity of heart failure until up to 2 years postoperatively.

Usefulness of Upper and Lower Limb Muscles Strength in the Evaluation of Clinical Severity of Heart Failure in Elderly Patients

Aim: Assess upper and lower limb functions in elderly with heart failure (HF) and evaluate its relation to HF severity. Methods: Handgrip strength (HGS) in kilograms (kgs.) of both hands using handle mechanical dynamometer and counting the repetitions (rep.) of stand and sit on a chair during 30 seconds [the 30 seconds chair-stand test (CST)] were used in 71 elderly (≥65 years old) patients with clinically stable HF and other matched 32 healthy elderly as a control. HF was diagnosed clinically, by plasma B-Type natriuretic peptide (BNP) and by echocardiography. The New York Heart Association (NYHA) functional classification of HF was used to obtain two groups: NYHA class I-II (33 patients), and NYHA class III (38 patients). Results: Showed significant decrease in both HGS and CST score in all HF patients (9.7 ± 4.4 kgs., 8.8 ± 3.1 rep., respectively) compared to controls (77.8 ± 11 kgs., 13.5 ± 1.1 rep., respectively, p Conclusion: Upper and lower limb muscles strength, assessed by two easy andinexpensive tests (HGS and CST), may reflect clinical severity of HF in elderly patients who cannot usually perform exercise tests. Its prognostic value requires further follow-up studies to verify.

Cardiac remodeling hypertensive patients with different forms of thyroid dysfunction

Objective . To analyze the changes in the structural and functional characteristics of the heart, clinical severity of heart failure (HF) and the levels of N-terminal fragment of the brain natriuretic peptide (NT-proBNP) in patients with arterial hypertension (HTN) and various forms of the thyroid dysfunction (TD). Design and methods. The total of 101 HTN patients were included in the study: 40 with hypothyroidism; 39 — with hyperthyroidism, 22 — without any TD. Control group consisted of 20 persons without any cardiovascular pathology and TD. Basic structural and functional parameters of the heart, serum levels of NT-proBNP were studied. Results . In patients with TD, HF was revealed significantly more often than in the group of AH without TD. There with patients with hypothyroidism had higher, HF functional class compared to the group of hyperthyroidism. In the group of HTN with hypothyroidism left ventricular (LV) hypertrophy and decrease of E/A ratio were observed, whereas patients with HTN and hyperthyroidism were characterized by LV dilatation and by a significant increase of serum NTproBNP level. Conclusions. In HTN patients with hyperthyroidism cardiac remodeling is characterized by the prevalence of LV dilatation, whereas in hypothyroidism LV hypertrophy with LV diastolic dysfunction dominate. Hyperthyroidism is also associated with increased NT-proBNP serum levels.

A novel method for the quantitative evaluation of diurnal respiratory instability in patients with heart failure: A pilot study

BackgroundThere is no established method to quantitatively measure the presence and the severity of respiratory instability (RI). The purpose of this pilot study was to propose a novel index of diurnal RI as a surrogate measure of clinical severity of heart failure (HF). Methods and resultsWe prospectively enrolled 60 patients with symptomatic HF [70±14 years, 75% male, and New York Heart Association (NYHA) functional classes II–IV] who underwent right heart catheterization (RHC), and recorded diurnal respiration using a nasal pressure sensor during bed rest while awake within 2 days before or after RHC. Non-uniformity of the breath-by-breath respiratory slopes during 15min calculated as the ratio of peak expiratory amplitude to corresponding peak-to-peak interval was assessed by histogram-based frequency distribution measurement, and was defined as the “RI-index”. The RI-index was significantly different among NYHA functional classes and was highest in NYHA class IV. The presence of atrial fibrillation (β coefficient: 0.300, p=0.01) and stroke volume index (β coefficient: −0.462, p<0.01) were independently associated with RI index among hemodynamic parameters. Furthermore, the high RI index above the median value was the independent predictor of the composite outcome of death from any cause, a life-threatening arrhythmia, and an unplanned hospitalization for worsening HF. ConclusionsThe RI index stratified functional severity of HF well, and was a significant independent predictor of poor outcomes.

Evaluation of N-Terminal Pro Brain Natriuretic Peptide as a biomarker for clinical severity of heart failure in pediatric population

Background and study aim: Brain Natriuretic Peptide (BNP) and N-Terminal pro-Brain Natriuretic Peptide (NT-pro BNP) are frequently used in the diagnosis of congestive heart failure (CHF), especially for distinguishing between patients with dyspnea of cardiac and pulmonary origin. The present work aimed at evaluating N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) as a biomarker for diagnosis of congestive heart failure (CHF) in pediatrics and as well as its severity and hence, helping early diagnosis of CHF in absence of rapid echocardiographic examination. Subjects and Methods: The patients group (group I) consisted of 45 children (Session [UserIDID] males and 21 females) aging between 45 days and 12 years. All having the inclusion criterion of CHF. They were subclassified into: group I-1 including 15 patients having dilated cardiomyopathy (DCM), group I-2 including 15 patients having congenital heart disease (CHD) and group I-3 including 15 patients that have developed CHF due to non-cardiac causes. The control group was formed of 15 healthy children (group II) matched in age and gender with the patients groups. All children were subjected to full history taking, physical examination, classification of clinical severity of CHF cases according to Modified Ross Score, imaging and laboratory investigations including serum level of NT-proBNP. Results: The study revealed that serum NT-proBNP showed a highly statistically significant increase in CHF cases three groups (I-1, I-2 and I-3) in comparison to the control group (group II) (P<0.001). NT-proBNP level showed highly statisticallysignificant positive correlation with CHF class of clinical severity (P<0.001). Regarding echocardiographic parameters NT-proBNP showed a highly significant positive correlation with left ventricular end diastolic dimensions (LVEDD) and left ventricular end systolic dimensions (LVESD), and a highly significant negative correlation with left ventricular (LV) ejection fraction (EF), fractional shortening (FS) and mitral valve E/A ratio. At cutoff level of 1500 pg/ml, the sensitivity of NT-proBNP as a diagnostic biomarker in children with CHF was 98% and the specificity was 100%. Conclusion: NT-proBNP is significantly statistically correlated with clinical severity of CHF and echocardiographic parameters of CHF cases of different causes .We highly recommend a long-term study on the value of the level of NT-proBNP as a prognostic risk parameter.

To Evaluate the Change in Brain Natriuretic Peptide Levels in Outpatients with Ischemic Cardiomyopathy and Its Association with Functional Capacity: A Pilot Study.

Literature is sparse on the clinical correlation of six minute walk test (6MWT) and Brain Natriuretic Peptide (BNP) levels in ischemic Cardiomyopathy (Ischemic CMP) patients. New York Heart Association (NYHA) classification is most commonly used for functional assessment of Heart Failure (HF), which is very subjective. This limitation is overcome by 6MWT which has prognostic significance in addition to assessment of level of functional impairment. Serum BNP correlate with clinical severity of HF as assessed by NYHA class. To evaluate the change in BNP levels in outpatients with ischemic CMP and its association with functional capacity. Sixty seven patients of established ischemic CMP by coronary angiography With Left Ventricular Ejection Fraction (LVEF) <40%, were recruited on an Outpatients Department (OPD) basis and assessed for baseline BNP levels and functional capacity (NYHA class and 6MWT). These patients were managed on OPD basis and the treatment was optimised and all the aggravating factors like uncontrolled diabetes, hypertension and anaemia were corrected. Patients were also advised life style modifications and cessation of smoking and alcohol consumption. All these patients were followed up for six months with optimum medical treatment and repeat 6MWT and BNP levels. Primary end point was change in the functional class and the BNP levels at six months. Statistical analysis was done with paired t-test and Pearson correlation for BNP levels and 6MWT/NYHA class. A total of 67 patients were enrolled, out of which 48 patients had six months follow up. Thirty two patients were in NYHA Class II and remaining was in NYHA Class III at the time of enrollment. At six months, 37 were in NYHA Class II and 11 in Class III. At enrollment, 37 cases were able to walk >300 m in six minutes and 11 cases walked < 300 m where as at six months 43 walked >300 m and five walked <300 m. As compared to baseline the mean distance covered in 6MWT showed significant improvement and with reduction in BNP levels at six months (p<0.001). Mean BNP levels correlated better with 6MWT (p <0.001) than NYHA class (p<0.67). In patients with established ischemic CMP with LVEF <40%, there is a significant reduction in BNP levels and improvement in 6MWT at six months with optimum medical therapy. A 6MWT correlated better with BNP levels than with NYHA class with a significant p-value. However, larger such studies and a longer duration of follow up is desirable to prove this association.

A single BNP measurement in acute heart failure does not reflect the degree of congestion

IntroductionMultiple studies found a significant correlation between B-type natriuretic peptide (BNP) level and clinical severity of heart failure (HF). We aim to study the ability of a single BNP measurement to predict the degree of congestion in acute systolic HF. MethodsPatients enrolled in the ESCAPE trial who were admitted with acute systolic HF were divided into tertiles according to baseline BNP level with comparison of the degree of congestion across tertiles using clinical signs of congestion as well as objective parameters of overload checked by the pulmonary artery catheter. ResultsA total of 251 cases (mean age, 56 years; 75% males) were included in the study after excluding patients with normal (n = 43) or extremely elevated BNP (n = 53) due to the known limited significance of BNP in predicting the degree of congestion in the latter 2 instances. These cases were divided into tertiles as follows: tertile 1, BNP less than or equal to 376 pg/mL; tertile 2, BNP 377 to 792 pg/mL; and tertile 3, BNP greater than or equal to 793 pg/mL. There were significant differences across the BNP tertiles in age (P = .03) and body mass index (P = .003). There were no differences between the 3 BNP tertiles with regard to the presence of rales (P = .533), jugular venous distension (P = .245), positive hepatojugular reflux (P = .224), hepatomegaly (P = .489), ascitis (P = .886), lower extremity edema (P = .068), or S3 gallop (P = .512). With regard to hemodynamic markers of congestion measured via the pulmonary artery catheter, there were no significant differences across the BNP tertiles in the right atrial pressure (P = .148), pulmonary capillary wedge pressure (P = .140), pulmonary artery systolic pressure (P = .155), pulmonary artery diastolic pressure (P = .246), and pulmonary artery mean pressure (P = .607). ConclusionAlthough longitudinal BNP follow-up may be valuable in reflecting the degree of congestion, looking at a single BNP measurement alone is not a good marker to predict the level of congestion and should not be used as a “stand-alone” test for determining aggressiveness of diuresis. Management should be guided by the entirety of physical examination, laboratory values, and hemodynamic parameters when available.

Anti-KCNQ1 K+ channel autoantibodies increase IKs current and are associated with QT interval shortening in dilated cardiomyopathy

Autoimmune-associated proarrhythmia in dilated cardiomyopathy (DCM) is poorly understood. Given the significance of KCNQ1 potassium channels in heart rhythm disorders, we hypothesized that circulating anti-KCNQ1 autoantibodies directly modulate cardiac electrophysiology in DCM patients. The purpose of this pilot study was to characterize ion channel autoantibodies in DCM targeting the cardiac repolarizing K(+) current, IKs, and the underlying KCNQ1 potassium channel. One hundred and fifty DCM patients were screened for anti-KCNQ1 autoantibodies using an enzyme-linked immunosorbent assay. Autoantibodies targeting the extracellular pore domain of the KCNQ1 channel were detected in 6% of study patients. Seropositive individuals exhibited significantly shorter corrected QT intervals when compared with seronegative patients (371 ± 39.9 ms vs. 408 ± 47.9 ms; P = 0.036). There was no difference in clinical severity of heart failure between groups. The functional significance of anti-KCNQ1 antibodies was determined in human embryonic kidney 293 cells expressing KCNQ1/KCNE1 using the whole-cell patch clamp technique. IKs recordings demonstrated a 2.7-fold increase in mean current density on exposure to patients' sera containing anti-KCNQ1 antibodies in contrast to seronegative controls (8.74 ± 1.44 pA/pF vs. 3.26 ± 0.36 pA/pF; P = 0.003). IKs enhancement was not associated with increased KCNQ1 protein levels or altered cell surface expression of the channel. Anti-KCNQ1 autoantibodies found in a subgroup of DCM patients are associated with QT interval shortening and increased IKs current.

Bundle branch block patterns and long-term outcomes in heart failure

The prognostic value of left and right bundle branch blocks (LBBB and RBBB) in hospitalized heart failure (HF) patients is unclear. We sought to determine the prognostic value of bundle branch blocks in patients hospitalized with heart failure. The associations of BBB type with death, HF hospitalizations or cardiovascular hospitalizations over a five year follow-up were examined within the EFFECT study of hospitalized patients fulfilling the Framingham criteria for acute heart failure. Multinomial logistic regression was used to determine associations with BBB type, and survival was assessed using multiple Cox regression analysis. Among 9082 patients (16.3% with LBBB; 7.2% with RBBB), LBBB was independently associated with lower systolic pressure, tachycardia and hyponatremia (odds ratio [OR] of 0.93 per 10 mmHg, 1.04 per 10 beats/min, and 0.84 per 10 mmol/L, respectively). Men and diabetics (OR of 2.11 and 1.35, respectively) had greater odds of RBBB. After multiple covariate adjustment (n=7319), patients with LBBB had increased risk of HF hospitalization with adjusted hazard ratio [HR] of 1.32 (95% CI; 1.20-1.46, p<0.001) and cardiovascular hospitalization with HR of 1.13 (95% CI; 1.04-1.23, p=0.003). LBBB was associated with increased mortality with adjusted HR of 1.10 (95% CI, 1.02-1.18; p=0.011) in 7910 analysed patients. RBBB did not predict significantly increased risk of either death or hospitalization. Heart failure patients presenting with LBBB had greater clinical severity of heart failure at presentation and greater risk of death and hospitalization for heart failure or cardiovascular disease than those without BBB. In contrast, RBBB did not independently predict worse outcomes.

Association of Left Ventricular Dilation at Listing for Heart Transplant With Postlisting and Early Posttransplant Mortality in Children With Dilated Cardiomyopathy

In patients with dilated cardiomyopathy, the magnitude of cardiac remodeling often correlates with the clinical severity of heart failure. We sought to determine whether measures of left ventricular (LV) dilation and systolic dysfunction in children with dilated cardiomyopathy at the time of listing for cardiac transplantation are associated with survival while waiting for and early after transplant. We analyzed echocardiographic data obtained within 6 months of listing for heart transplant and clinical data from 261 children with dilated cardiomyopathy who were included in both the Pediatric Cardiomyopathy Registry and the Pediatric Heart Transplant Study. Median time to listing after diagnosis was 1.9 months and to transplant after listing was 0.8 months. There were 42 deaths (29 waiting and 13 within 6 months after transplant). We found a significant age-dependent association of LV end-diastolic dimension z score (n=204, 31 deaths) with death controlling for race, transplant status, and medical insurance. The association was strongest for infants younger than 6 months at diagnosis (hazard ratio 1.47, P=0.008) and was not significant in children older than 5 years at diagnosis. A similar interaction was identified between age and LV end-systolic dimension z score (P=0.04). Neither LV function nor mass was associated with death, overall, or in subgroups. The severity of LV dilation at listing for heart transplant is associated with outcome in infants and young children with dilated cardiomyopathy, whereas the severity of LV systolic dysfunction is not. These findings should be considered in risk stratification of these children at listing.

MR spectroscopy in heart failure—clinical and experimental findings

Magnetic resonance spectroscopy (MRS) allows for the non-invasive detection of a wide variety of metabolites in the heart. To study the metabolic changes that occur in heart failure, (31)P- and (1)H-MRS have been applied in both patients and experimental animal studies. (31)P-MRS allows for the detection of phosphocreatine (PCr), ATP, inorganic phosphate (Pi) and intracellular pH, while (1)H-MRS allows for the detection of total creatine. All these compounds are involved in the regulation of the available energy from ATP hydrolysis via the creatine kinase (CK) reaction. Using cardiac MRS, it has been found that the PCr/CK system is impaired in the failing heart. In both, patients and experimental models, PCr levels as well as total creatine levels are reduced, and in severe heart failure ATP is also reduced. PCr/ATP ratios correlate with the clinical severity of heart failure and, importantly, are a prognostic indicator of mortality in patients. In addition, the chemical flux through the CK reaction, measured with (31)P saturation transfer MRS, is reduced more than the steady-state levels of high-energy phosphates in failing myocardium in both experimental models and in patients. Experimental studies suggest that these changes can result in increased free ADP levels when the failing heart is stressed. Increased free ADP levels, in turn, result in a reduction in the available free energy of ATP hydrolysis, which may directly contribute to contractile dysfunction. Data from transgenic mouse models also suggest that an intact creatine/CK system is critical for situations of cardiac stress.

Increased circulating big endothelin-1, endothelin-1 and atrial natriuretic peptide in infants and children with heart failure secondary to congenital heart disease

In order to characterize the changes of five neurohormones in pediatric patients with varying degrees of congestive heart failure (CHF) secondary to congenital heart disease (CHD), we measured plasma neurohormone levels by using radioimmunoassay or high-performance liquid chromatography in 81 subjects including 13 normal children and 68 pediatric patients with CHD. Patients with CHF ( n=27) had elevated levels of big endothelin-1 (big ET-1) (29.5±1.6 vs. 18.1±2.1 pg/ml, p<0.001), endothelin-1 (ET-1) (17.9±1.7 vs. 7.8±1.7 pg/ml, p<0.001) and norepinephrine (505.6±65.6 vs. 219.6±23.3 pg/ml, p<0.01) as compared with healthy control subjects ( n=13). Plasma norepinephrine levels (505.6±65.6 vs. 230.0±8.0 pg/ml, p<0.001) and atrial natriuretic peptide (35.5±4.2 vs. 7.6±0.6 pg/ml, p<0.001) in the 27 patients with CHF were significantly higher than in the 41 patients without CHF. There was also a highly significant stepwise increase in big ET-1, atrial natriuretic peptide and norepinephrine according to the severity of heart failure. Our results suggest that increased circulating neurohormonal activity in CHD relates to the presence and clinical severity of heart failure in children. Plasma levels of big ET-1 and ET-1 were not only significant markers of CHF but also correlated well with the severity of CHF in CHD with left-to-right shunt.

Mitral regurgitation: impaired systolic function, eccentric hypertrophy, and increased severity are linked to lower phosphocreatine/ATP ratios in humans.

A number of phosphorus (31P) magnetic resonance spectroscopy (MRS) studies link alterations of high-energy phosphate metabolism in valvular disease and cardiomyopathy to the clinical severity of heart failure. However, correlations between MRS and indexes of ventricular dysfunction are inconclusive to date. We examined whether changes in 31P MRS are associated with the impaired contractility, which predisposes to chronic congestive heart failure in patients with mitral regurgitation. Thirteen normal control subjects and 22 patients with echocardiographically characterized chronic mitral regurgitation were studied by 31P MRS. The apical phosphocreatine-to-ATP ratio (PCr/ATP) was lower in severe disease (P<.02) and those on therapy (n=13, 1.29+/-0.29, P<.01) in contrast to control subjects (n=13, 1.61+/-0.3). Compared to those with mild mitral regurgitation, patients with more severe incompetence had lower mean myocardial PCr/ATP ratios (mild, n=6, 1.73 [0.17], P<.05 and P<.01; moderate, n=5, 1.49 [0.18], P<.05; and severe, n=1, 1.29 [0.32], P<.01). PCr/ATP in those referred for mitral valve replacement was lower (n=8, 1.17+/-0.23) although not significantly decreased compared with the ratio among subjects on medical therapy alone (n=5, 1.48+/-0.29). PCr/ATP correlated with the end-systolic diameter (r2=.7, P<.001), end-diastolic diameter (r2=.32, P<.05), left ventricular wall thickness (r2=.38, P<.01), left atrial dimension (r2=.36, P<.05), and derived measurements such as the percent fractional shortening (2=.5, P<.01), and left ventricular mass/body surface area (r2=.5, P<.001) but not with wall stress. These results demonstrate that abnormalities of PCr/ATP in mitral regurgitation are related to disease severity as measured by dimensional indexes of left ventricular dilatation. They suggest that impaired high-energy phosphate metabolism is a marker of hypertrophy and heart failure.

Tumor Necrosis Factor and Steroid Metabolism in Chronic Heart Failure: Possible Relation to Muscle Wasting

Objectives. We sought to assess the possible relations between clinical severity of chronic heart failure and catabolic factors, specifically tumor necrosis factor (TNF), soluble TNF receptors 1 and 2 (sTNFR-1 and sTNFR-2), cortisol, testosterone and dehydroepiandrosterone (DHEA).Background. Chronic heart failure is associated with loss of muscle bulk that may be related to alteration of the balance between catabolism and anabolism.Methods. Sixty-three patients (average age ±SD 60.4 ± 11.3 years) with stable chronic heart failure and 20 control subjects aged 52.8 ± 11.4 years were studied. We measured body mass index (BMI) and obtained maximal incremental exercise testing with metabolic gas exchange measurements and measurements of venous levels of TNF, sTNFR-1 and sTNFR-2, cortisol and DHEA.Results. There was no difference in total TNF-alpha levels between patients and control subjects (9.76 ± 8.59 vs. 6.84 ± 2.7 pg/ml). sTNFR-1 (128.9 ± 84.5 vs. 63.6 ± 23.3 pg/ml, p < 0.003) and sTNFR-2 (250.1 ± 109.5 vs. 187.9 ± 92.2 pg/ml, p = 0.03) were higher in patients. DHEA was lower in patients (9.88 ± 6.94 vs. 15.64 ± 8.33 nmol/liter, p = 0.004). The ratio of log cortisol to log DHEA correlated with log TNF level (r = 0.50, p < 0.001 for the patients alone; r = 0.48, p < 0.001 for the group as a whole). Peak oxygen consumption correlated with both sTNFR-1 and sTNFR-2 (r = −0.51, p < 0.001 and r = −0.39, p < 0.001, respectively). There was a negative correlation between BMI and TNF levels (r = −0.43, p < 0.001 for the patients) and the cortisol/DHEA ratio (r = −0.32, p = 0.01 for the patients).Conclusions. There is an increase in TNF and its soluble receptors in chronic heart failure. This increase is associated with a rise in the cortisol/DHEA (catabolic/anabolic) ratio. These changes correlate with BMI and clinical severity of heart failure, suggesting a possible etiologic link.