Heart Failure Patients With Reduced Left Ventricular Ejection Fraction Research Articles

Multicenter prospective observational study to clarify the current status and clinical outcome in Japanese patients who have an indication for implantable cardioverter defibrillator (ICD) or wearable cardioverter defibrillator (WCD) (TRANSITION JAPAN‐ICD/WCD study): Rationale and design of a prospective, multicenter, observational, comparative study

AbstractBackgroundDespite the positive impact of implantable cardioverter defibrillators (ICDs) and wearable cardioverter defibrillators (WCDs) on prognosis, their implantation is often withheld especially in Japanese heart failure patients with reduced left ventricular ejection fraction (HFrEF) who have not experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) for uncertain reasons. Recent advancements in heart failure (HF) medications have significantly improved the prognosis for HFrEF. Given this context, a critical reassessment of the treatment and prognosis of ICDs and WCDs is essential, as it has the potential to reshape awareness and treatment strategies for these patients.MethodsWe are initiating a prospective multicenter observational study for HFrEF patients eligible for ICD in primary and secondary prevention, and WCD, regardless of device use, including all consenting patients. Study subjects are to be enrolled from 31 participant hospitals located throughout Japan from April 1, 2023, to December 31, 2024, and each will be followed up for 1 year or more. The planned sample size is 651 cases. The primary endpoint is the rate of cardiac implantable electronic device implementation. Other endpoints include the incidence of VT/VF and sudden death, all‐cause mortality, and HF hospitalization, other events. We will collect clinical background information plus each patient's symptoms, Clinical Frailty Scale score, laboratory test results, echocardiographic and electrocardiographic parameters, and serial changes will also be secondary endpoints.ResultsNot applicable.ConclusionThis study offers invaluable insights into understanding the role of ICD/WCD in Japanese HF patients in the new era of HF medication.

Heart failure and catheter ablation of atrial fibrillation: Navigating the difficult waters of heart failure phenotypes

The use of catheter ablation of atrial fibrillation (AFA) is increasing and it has now been extended to include higher risk patients with heart failure (HF), based on evidence from observational studies and meta-analyses of randomized controlled trials (RCTs) indicating it as safe and beneficial in terms of quality of life, AF recurrence and hospital readmissions in the short-to-middle term. However, the RCTs so far have been relatively small with short follow-up, and few larger trials with long follow-up inconclusive about hard outcomes for large patient crossover undermining the robustness of the results. Importantly, most RCTs involved HF patients with reduced left ventricular ejection fraction (HFrEF). In contrast, most observational studies show that the majority of ablated HF patients in clinical practice have a preserved ejection fraction (HFpEF), a condition representing roughly half of all HF patients. This article provides an overview of the available scientific evidence in this clinical field and examines the current guideline recommendations. In the absence of robust evidence-based research, the recommendations on AFA in HF may be inconsistent or abstain from taking firm positions, particularly regarding AFA in HFpEF. There is need for clinical research in such a surprisingly orphan setting, in parallel with the current attempts to sort out the knotty question of the HF phenotypes, in particular, again, of the HFpEF phenotypes.

The impact of asymptomatic ventricular arrhythmias on the outcome of heart failure patients with reduced ejection fraction

BackgroundVentricular arrhythmias cause a significant proportion of sudden deaths. Several studies demonstrate a high prevalence of ventricular arrhythmias in patients with heart failure regardless of the etiology. The aim of this study was to determine the prevalence of silent ventricular arrhythmias in ambulatory heart failure patients with reduced left ventricular ejection fraction (HFrEF) and its correlation to the prognosis.ResultsFour hundred (400) ambulatory HFrEF patients on maximum tolerated doses of heart failure medications were included. Holter monitoring for 7 days was done in all patients searching for silent ventricular arrhythmias. The patients were followed-up for one year to detect the occurrence of major adverse cardiovascular events. We divided the study population into 2 groups based on an LVEF cutoff value of 30% (Group A < 30%, Group B ≥ 30%). Holter monitoring revealed ventricular arrhythmias in 304 patients. Patients with left ventricular ejection fraction (EF) < 30% (Group A) had more complex ventricular arrhythmias in the form of frequent Premature ventricular contractions (PVCs) of ≥ 5% and or non-sustained ventricular tachycardia (NSVT) runs. Furthermore, Among Group A, more major cardiovascular events were observed. Multivariate regression analysis showed that frequent PVCs and severely reduced LVEF were the strongest independent predictors of major cardiovascular events.Conclusionsventricular arrhythmias are common in HFrEF patients even in the compensated status. Both, left ventricular systolic function and the PVCs burden were found to be the strongest predictors of major adverse cardiovascular events.

Prognostic Significance of Cardiac 123I-MIBG SPECT Imaging in Heart Failure Patients With Preserved Ejection Fraction

ObjectivesThe authors sought to elucidate the prognostic value of cardiac sympathetic nerve dysfunction as evaluated using iodine-123-labeled metaiodobenzylguanidine (123I-MIBG) single-photon emission computed tomography (SPECT) imaging in patients with heart failure (HF) with preserved left ventricular ejection fraction (HFpEF). BackgroundCardiac sympathetic nerve dysfunction assessed by 123I-MIBG imaging is associated with poor outcomes in chronic HF patients with reduced left ventricular ejection fraction (HFrEF). However, no information is available on the prognostic vale of cardiac 123I-MIBG SPECT imaging in patients with HFpEF. MethodsWe studied 148 patients admitted for acute decompensated HF (ADHF) with nonischemic HFpEF and who underwent cardiac 123I-MIBG imaging at discharge. The cardiac 123I-MIBG heart-to-mediastinum ratio (H/M) was measured on the delayed planar image (late H/M). SPECT analysis of the delayed image was conducted, and the tracer uptake in all 17 regions on the polar map was scored on a 5-point scale by comparison with a sex-matched normal control database. The total defect score (TDS) was calculated by summing the score of each of the 17 segments. The primary endpoint was the association between TDS and cardiac events (the composite of emergent HF hospitalization and cardiac death). ResultsDuring a mean follow-up period of 2.4 ± 1.6 years, 61 patients experienced cardiac events. TDS was significantly associated with cardiac events after multivariate Cox adjustment (P < 0.0001). Patients with high TDS levels had a significantly greater risk of cardiac events than those with middle or low TDS levels (63% vs 40% vs 20%, respectively; P < 0.0001; HR: 4.69; 95% CI: 2.29 to 9.61; and HR: 2.46; 95% CI: 1.14 to 5.29). C-statistic of TDS was 0.730 (95% CI: 0.651 to 0.799), which was significantly higher than that of late H/M (0.607; 95% CI: 0.524 to 0.686; P = 0.0228). ConclusionsCardiac 123I-MIBG SPECT imaging provided useful prognostic information in nonischemic ADHF patients with HFpEF. (Clinical Trial: Osaka Prefectural Acute Heart Failure Syndrome Registry [OPAR]: UMIN000015246)

Sacubitril/valsartan improves heart failure functional class, left ventricular systolic and diastolic function and neurohumoral status in patients with anthracycline-induced cardiomyopathy

Abstract Anthracycline-induced cardiomyopathy (AC-CMP) is more resistant or even refractory to conventional heart failure (HF) treatments and has a higher mortality rate as compared to HF associated with other diseases. Sacubitril/valsartan (S/V) significantly reduces cardiovascular mortality and hospitalization rate in HF patients with reduced left ventricular ejection fraction (HFrEF). There is lack of evidence of S/V efficacy and safety in patients with AC-CMP. We aimed to assess the efficacy and tolerability of S/V in patients with AC-CMP. Methods We enrolled 20 patients with anthracycline-induced HFrEF who met the indication criteria for S/V. Median age was 61 [51.5; 67], 100% women, 8 (40%) hypertensive, 1 (5%) diabetic. Seventeen (85%) patients had breast and 3 (15%) hematological cancers. Median time from anthracycline therapy was 3 [1; 11] years. Surgery due to cancer and radiation therapy were performed in 15 (75%) cases. All patients had been receiving ACE inhibitors or angiotensin II receptor blockers and were switched to S/V. 85% of patients were treated with beta-blockers, 60% – mineralocorticoid antagonists, 50% – loop diuretics. The exam (at admission and after 6 months) included 6-MWT, echo/speckle tracking, creatinine, potassium and NTproBNP level. Results Eleven (55%) patients achieved the target dose of S/V. The mean S/V dose was 289±149.1 mg. Symptomatic hypotension, hyperpotassemia or creatinine level elevation were the reasons for S/V dose reduction in 8, 1 and 2 patients, respectively. S/V wasn't withdrawn in any patient. No hospitalization due to HF or need for loop diuretics increase occurred during the follow-up. After 6 months 6-MWD increased from 416 [347.5; 477.5] to 465 [395; 513.5] m, p=0.0004. NYHA functional class improved in 50% of patients. We revealed LVEDVI decrease (61.7 [55.9; 71.6] to 57.1 [53.4; 60.1] ml/m2 p=0.002), LVEF and GLS increase (39 [34.7; 41] to 45 [39; 47]%, p=0.001 and 11 [8.7; 13.9] to 13.4 [11.9; 15.5]%, p=0.002, respectively), LAVI decrease (40.7 [32; 43.9] to 31.3 [28.6; 37.4] ml/m2, p=0.003), E/A and E/e ratios decrease (1.37 [0.7; 2.23] to 0.69 [0.64; 0.83], p=0.04, and 13 [11.3; 17.8] to 10.7 [6.9; 13.6], p=0.01, respectively). NTproBNP blood level declined from 1659 [1090; 2316] to 377 [206.8; 920] pg/ml, p&amp;lt;0.001. There was change in serum creatinine level but in normal ranges (from 70.3 [66.8; 80; 6] to 77 [68.6; 96.3] micromol/l, p=0.02). No significant changes in potassium level were observed. Conclusions In this pilot study S/V was well tolerated in patients with AC-CMP, but cardiologic assessment was needed for accurate dose adjustment. Therapy with S/V was associated with improvement in HF functional class and LV systolic and diastolic function as well as neurohumoral status in patients with AC-CMP. Funding Acknowledgement Type of funding source: None

Automatic positive airway pressure for obstructive sleep apnea in heart failure with reduced ejection fraction

BackgroundModerate-to-severe obstructive sleep apnea (OSA) is highly prevalent in heart failure patients with reduced left ventricular ejection fraction (HFrEF), and is associated with worsening cardiac function and increased mortality.ObjectivesThe automatic positive airway pressure (APAP) trial tested the impact of APAP treatment on changes for the pre-specified endpoints: changes in peak oxygen uptake (peak VO2), percent-predicted peak VO2 and oxygen uptake at anaerobic threshold (VO2-AT).MethodsThis randomized, controlled pilot study included patients with chronic, stable HFrEF who had moderate-to-severe OSA. Patients were randomized 1:1 to either APAP (AutoSet™, ResMed) or nasal strips (control) for 6 months.Results76 patients have been randomized and 58 had complete data for final analysis. There was a statistically significant change in the APAP intervention arm for the primary endpoint percent-predicted peak VO2 in comparison to control (67 ± 17 to 73 ± 19%; p = 0.01). Additional primary endpoints peak VO2 and VO2-AT showed a trend in increase in the APAP group. Moreover, there were significant improvements within the APAP group for hypoxemia, left ventricular function and quality of life from baseline to 6 months, but not within the control group (p = 0.001 and p = 0.037, respectively).ConclusionAPAP intervention was shown to significantly improve outcome compared to control group, represented in percent-predicted peak VO2, an established surrogate marker for cardiovascular prognosis in HFrEF. APAP has additional beneficial effects on hypoxemia, cardiac function and quality of life.

Clinical significane of two-dimensional speckle tracking technique in the evaluation of diagnosis and prognosis of heart failure with left ventricular ejection fraction preservation

Objective To observe the clinical effect of two-dimensional speckle tracking technique in diagnosis and prognosis evaluation of heart failure with left ventricular ejection fraction preservation. Methods A total of 64 heart failure patients with reduced left ventricular ejection fraction (HFNEF) and 64 healthy volunteers in the Integrated Traditional Chinese and Western Medicine Hospital of Wenzhou were selected from July 2016 to July 2018.Conventional echocardiography and two-dimensional speckle tracking were performed in all subjects.The hemodynamic parameters and strain parameters of two-dimensional speckle tracking were recorded.The differences of conventional echocardiographic parameters and two-dimensional speckle tracking strain parameters in different subjects were analyzed. Results The E/A (0.79±0.24) and E/E' value (18.93±3.41) in HFNEF patients had statistically significant differences compared with healthy subjects [(1.28±0.35) and (6.84±1.37)] (t=9.507, 23.294; P=0.000, 0.000). There were no statistically significant differences in HR, LAD, LVD, LVSD, LVPWD, LVEF and LVFS between HFNEF patients [(71.37±5.93)times/min, (35.32±4.37)mm, (47.13±5.01)mm, (9.24±1.76)mm, (9.35±1.82)mm, (63.98±5.37)%, (35.49±4.46)%] and healthy subjects [(70.14±5.28)times/min, (37.64±4.69)mm, (49.26±5.54)mm, (9.39±1.82)mm, (9.48±1.90)mm, (66.35±5.41)%, (34.02±4.17)%] (t=0.384-1.628; P=0.102-0.564). In HFNEF patients, the anterior septum, anterior wall, posterior wall, inferior wall and posterior wall of apical segment of left ventricle, the inferior wall and posterior wall of papillary muscle and the posterior wall, inferior wall and posterior wall of basal segment, SRs and ROT of left ventricle were significantly lower than those of healthy subjects, while GLS (-13.52±4.18) and GCS (-10.43±3.85) of left ventricle in HFNEF patients were significantly higher than those of healthy subjects [(-19.89±4.61) and (-15.67±4.24)] (t=8.947~14.063; P=0.000-0.000<0.05). After treatment, the clinical symptoms of HFNEF patients improved significantly in the whole apical segment of left ventricle, inferior and posterior wall of papillary muscle segment, posterior lateral wall, inferior wall, posterior wall SRs and left ventricular GLS, GCS and ROT (t=7.258-13.193; P=0.000-0.000<0.05). Two-dimensional strain GLS and GC values in HFNEF patients were negatively correlated with E/A values and positively correlated with E/E' value (r=-0.817, -0.763; P=0.004, 0.012<0.05), while two-dimensional strain ROT results were positively correlated with E/A values and negatively correlated with E/E' values (r=-0.805, -0.759; P=0.006, 0.014<0.05). Conclusion Left ventricular systolic function damage has occurred in HFNEF patients.Two-dimensional speckle tracking technique is highly sensitive to the changes of myocardial systolic function for HFNEF patients.It has high clinical value in the diagnosis and prognosis evaluation of HFNEF.Relevant clinical workers should pay attention to it. Key words: Two-dimensional speckle tracking technique; Echocardiography; Heart failure with left ventricular ejection fraction preservation; Relevance; Left ventricle; Myocardial dysfunction; Diagnosis; Prognostic evaluation

Effect of combined aerobic and resistance training on peak oxygen consumption, muscle strength and health-related quality of life in patients with heart failure with reduced left ventricular ejection fraction: a systematic review and meta-analysis

ObjectiveThe aim of this study was to investigate the effects of combined aerobic and resistance training on peak oxygen consumption (peak VO2), minute ventilation/carbon dioxide production (VE/VCO2 slope), muscle strength and health-related quality of life (HRQoL) in heart failure patients with reduced left ventricular ejection fraction (HFrEF). MethodsWe searched Cochrane, Pubmed, and PEDro (from the earliest date available to September 2018) for RCTs that evaluated the effects of combined aerobic and resistance training in HFrEF patients. Weighted mean differences (WMD), standardized mean difference (SMD), and 95% confidence interval (CI) were calculated. Results39 studies met the study criteria, including 2008 patients, 14 compared combined aerobic and resistance training versus aerobic training, and 25 compared combined aerobic and resistance training versus control. Compared to aerobic training, combined aerobic and resistance training resulted in improvement in muscle strength SMD 0.7 (95% CI: 0.3 to 1.0 N = 167) and, HRQoL WMD –2.6 (95% CI: −5.0 to −0.1 N = 138). A nonsignificant difference in peak VO2 and VE/VCO2 slope was found for participants in the combined aerobic and resistance training group compared with aerobic training group. Compared to control, combined aerobic and resistance training resulted in improvement in peak VO2 WMD 2.9 (95% CI: 1.6 to 4.4 N = 638), muscle strength SMD 0.64 (95% CI: 0.4 to 0.9 N = 315) and, HRQoL WMD –9.8 (95% CI: −15.2 to −4.5 N = 524). ConclusionsCombined aerobic and resistance training improves peak VO2, muscle strength and HRQoL and should be considered as a component of care of HFrEF patients.

Empagliflozin in heart failure patients with reduced ejection fraction: a randomized clinical trial (Empire HF)

BackgroundData from recent cardiovascular outcome trials in patients with type 2 diabetes (T2D) suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors can prevent development of heart failure (HF) and prolong life in patients without HF. Ongoing event-driven trials are investigating whether the same effect is present in patients with well-defined HF. The mechanism behind the effect of SGLT2 inhibitors in patients with T2D and the potential effect in patients with overt HF is presently unknown.MethodsThis is a randomized, double-blinded, placebo-controlled, parallel group, clinical trial including HF patients with reduced left ventricular ejection fraction (HFrEF) with an ejection fraction ≤ 40% on optimal therapy recruited from specialized HF clinics in Denmark. The primary aim is to investigate the effect of the SGLT2 inhibitor empagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP). Secondary endpoints include cardiac biomarkers, function and hemodynamics, metabolic and renal parameters, daily activity level, and quality of life. Patients are assigned 1:1 to 90 days treatment with empagliflozin 10 mg daily or placebo. Patients with T2D are required to be on recommended doses of anti-glycemic therapy with a hemoglobin A1c (HbA1c) of 6.5–10.0% (48–86 mmol/mol). To show a between-group difference in the change of NT-proBNP of 30%, a total of 189 patients will be included.DiscussionThe Empire HF trial will elucidate the effects and modes of action of empagliflozin in HFrEF patients with and without T2D and provide important mechanistic data which will complement ongoing event-driven trials.Trial registrationClinicaltrialsregister.eu, EudraCT Number 2017-001341-27. Registered on 29 May 2017.ClinicalTrials.gov, NCT03198585. Registered on 26 June 2017.

Adaptive servo-ventilation to treat central sleep apnea in heart failure with reduced ejection fraction: the BadOeynhausen prospective ASV registry.

Central sleep apnea (CSA) is highly prevalent in heart failure patients with reduced left ventricular ejection fraction (HF-REF). The Bad Oeynhausen Adaptive Servo-ventilation (ASV) registry (NCT01657188) was designed to investigate whether treatment of CSA with ASV improved survival in HF-REF patients; the effects of ASV on symptoms and cardiopulmonary performance were also investigated. From January 2004 to October 2013, the registry prospectively enrolled HF-REF patients [NYHA class ≥ II, left ventricular ejection fraction (LVEF) ≤ 45%] with moderate to severe predominant CSA [apnea-hypopnea index (AHI) ≥ 15/h]. ASV-treated patients were followed up at 3, 6, 12 and 24months, including natriuretic peptide concentrations, blood gas analyses, echocardiography, 6-min walk distance (6MWD), and cardiopulmonary exercise (CPX) testing. 550 patients were included [age 67.7 ± 10 years, 90% male, 52% in NYHA class ≥ III, LVEF 29.9 ± 8%, AHI 35.4 ± 13.6/h, and time with nocturnal oxygen saturation < 90% (T < 90%) 58 ± 73min]; ASV was prescribed to 224 patients. Over a median follow-up of 6.6years, 109 (48.7%) ASV-treated patients and 191 (58.6%) controls died (adjusted Cox modelling hazard ratio of 0.95, 95% confidence interval 0.68-1.24; p = 0.740); older age, lower LVEF, impaired renal function, low sodium concentration, and nocturnal hypoxemia were significant predictors of mortality. Patient reported NYHA functional class improved in the ASV group, but LVEF, CPX, 6MWD, natriuretic peptides and blood gases remained unchanged. Long-term ASV treatment of predominant CSA in HF-REF patients included in our registry had no statistically significant effect on survival. ASV improved HF symptoms, but had no significant effects on exercise capacity, LVEF, natriuretic peptide concentrations or blood gases during follow-up as compared to control patients.

IMPROVED QUALITY OF LIFE WITH AUTOMATIC POSITIVE AIRWAY PRESSURE FOR OBSTRUCTIVE SLEEP APNEA IN HEART FAILURE WITH REDUCED EJECTION FRACTION: A RANDOMISED CONTROLLED TRIAL

Moderate to severe obstructive sleep apnea (OSA) is present in about 20% of heart failure patients with reduced left ventricular ejection fraction (HF-REF). OSA in HF-REF patients is linked with impaired quality of life (QoL), progressive worsening in cardiac function and impaired prognosis. The

Teasing Apart Heart Failure With Preserved Ejection Fraction Phenotypes With Echocardiographic Imaging: Potential Approach to Research and Clinical Practice.

Phenotyping heart failure represents a major challenge for both research studies and clinical practice. Large-scale clinical trials have failed to achieve meaningful improvement in clinical outcomes with different pharmacological agents in patients with heart failure and preserved left ventricular ejection fraction. Therefore, an alternative scheme for phenotyping heart failure is needed, which is both pathophysiologically distinct and practical for routine clinical application. Heart failure is a syndromic diagnosis broadly based on clinical features, physical findings, and serum biomarkers. Although the assessment of exercise hemodynamics and invasive estimation of filling pressures may be necessary, it is typically confirmed and phenotyped by the imaging data. Phenotyping heart failure represents a major challenge despite decades of ongoing research, vast clinical experience in the field, and multiple iterations of published guidelines. Left ventricular ejection fraction (LVEF) remains the major phenotyping tool endorsed by multiple cardiology societies. However, it has multiple limitations especially in patients with heart failure with preserved LVEF (HFpEF), and many have questioned the current approach to phenotyping of heart failure but no alternative, widely accepted, scheme (which is both clinically relevant and practical) has been offered.1 The existing phenotyping approach to heart failure is based on the premise of LVEF as a surrogate marker for left ventricular systolic performance and, in turn, prognosis. Heart failure patients with reduced LVEF (HFrEF) are assumed to have systolic heart failure, whereas many heart failure patients have preservation of LVEF and are commonly labeled as HFpEF. This assumption makes LVEF the primary marker of heart failure and excludes other important abnormalities that can create the heart failure syndrome. Furthermore, LVEF is an imperfect marker even for assessment of systolic function: it has high interobserver variability, it mainly reflects radial shortening, it is load dependent, and it does not reflect the remodeling pattern of the …

Elevation of plasma oncostatin M in heart failure.

Oncostatin M (OSM) is an inflammatory cytokine of the gp130 family. OSM could participate in adverse cardiovascular remodeling through regulation of FGF23. OSM levels were determined in 80 heart failure patients with reduced left ventricular ejection fraction (HFrEF). OSM levels are significantly increased in HFrEF patients compared with healthy subjects. We have also demonstrated that, in HFrEF patients, plasma OSM levels are correlated to parathyroid hormone PTH(1-84) and 1,25(OH)2D, two other biomarkers related to bone and mineral metabolism and associated to adverse cardiovascular outcomes. OSM concentrations are elevated in HFrEF patients and could interplay with parathyroid hormone and vitamin D impacting cardiovascular function. Nevertheless, the prognostic value of OSM testing appears limited.

Effects of adaptive servo-ventilation on ventricular arrhythmias in patients with stable congestive heart failure and sleep-disordered breathing

Congestive heart failure patients with reduced left ventricular ejection fraction (HFrEF) and sleep-disordered breathing (SDB) are at an increased risk of nocturnal cardiac arrhythmias. SDB can be effectively treated with adaptive servo-ventilation (ASV). Therefore, we tested the hypothesis that ASV therapy reduces nocturnal arrhythmias and heart rate in patients with HFrEF and SDB. In a non-prespecified subanalysis of a multicenter randomized controlled trial (ISRCTN04353156), 20 consecutive patients with stable HFrEF (age 67 ± 9 years; left ventricular ejection fraction, LVEF 32 ± 7 %) and SDB (apnea–hypopnea index, AHI 48 ± 20/h) were randomized to either an ASV therapy (n = 10) or an optimal medical treatment alone group (controls, n = 10). Polysomnography (PSG) with blinded centralized analysis and scoring was performed at baseline and at 12 weeks. The electrocardiograms (ECG) of the PSGs were analyzed with long-term (24-h) Holter ECG software (QRS-Card™ Cardiology Suite; Pulse Biomedical Inc., King of Prussia, PA, USA). There was a decrease in ventricular extrasystoles (VES) per hour of recording time in the ASV group compared to the control group (−8.1 ± 42.4 versus +9.8 ± 63.7/h, p = 0.356). ASV reduced the number of ventricular couplets and nonsustained ventricular tachycardias (nsVT) compared to the control group (−2.3 ± 6.9 versus +2.1 ± 12.7/h, p = 0.272 and −0.1 ± 0.5 versus +0.1 ± 1.1/h, p = 0.407, respectively). Mean nocturnal heart rate decreased in the ASV group compared to the controls (−2.0 ± 2.7 versus +3.9 ± 11.5/min, p = 0.169). The described changes were not significantly different between the groups. In HFrEF patients with SDB, ASV treatment may reduce nocturnal VES, couplets, nsVT, and mean nocturnal heart rate. The findings of the present pilot study underscore the need for further analyses in larger studies.

Tumor necrosis factor-α impairs adiponectin signalling, mitochondrial biogenesis, and myogenesis in primary human myotubes cultures.

Skeletal muscle metabolic changes are common in patients with chronic heart failure (HF). Previously, we demonstrated a functional skeletal muscle adiponectin resistance in HF patients with reduced left ventricular ejection fraction (HFrEF). We aimed to examine the impact of adiponectin receptor 1 (AdipoR1) deficiency and TNF-α treatment on adiponectin signaling, proliferative capacity, myogenic differentiation, and mitochondrial biogenesis in primary human skeletal muscle cells. Primary cultures of myoblasts and myotubes were initiated from the musculus vastus lateralis of 10 HFrEF patients (left ventricular ejection fraction; 31.30 ± 2.89%) and 10 age- and gender-matched healthy controls. Healthy control cultures were transfected with siAdipoR1 and/or exposed to TNF-α (10 ng/ml; 72 h). Primary cultures from HFrEF patients preserved the features of adiponectin resistance in vivo. AdipoR1 mRNA was negatively correlated with time to reach maximal cell index (r = -0.7319, P = 0.003). SiRNA-mediated AdipoR1 silencing reduced pAMPK (P < 0.01), AMPK activation (P = 0.046), and myoblast proliferation rate (xCELLigence Real-Time Cellular Analysis; P < 0.0001). Moreover, TNF-α decreased the mRNA expression of genes involved in glucose (APPL1, P = 0.0002; AMPK, P = 0.021), lipid (PPARα, P = 0.025; ACADM, P = 0.003), and mitochondrial (FOXO3, P = 0.018) metabolism, impaired myogenesis (MyoD1, P = 0.053; myogenin, P = 0.048) and polarized cytokine secretion toward a growth-promoting phenotype (IL-10, IL-1β, IFN-γ, P < 0.05 for all; Meso Scale Discovery Technology). Major features of adiponectin resistance are retained in primary cultures from the skeletal muscle of HFrEF patients. In addition, our results suggest that an increased inflammatory constitution contributes to adiponectin resistance and confers alterations in skeletal muscle differentiation, growth, and function.

Abstract 75: Practice-level Variation in use of Recommended Medications among Outpatients with Heart Failure: Insights from the NCDR PINNACLE Program

Background: Beta-blockers (BB) and angiotensin converting enzyme inhibitors (ACE)/angiotensin receptor blockers (ARB) are guideline recommended therapies for ambulatory heart failure patients with reduced left ventricular ejection fraction (HFREF). Real-world use of these therapies is suboptimal. Whether variations in treatment are dominated by practice-level or patient-level factors is unknown. Methods: Practices participating in the NCDR PINNACLE program, a national office-based cardiac quality improvement registry, between July 2008 and December 2010 were evaluated. Rates of treatment with BB and ACE/ARB were evaluated in patients with HFREF (EF ≤40%) and no documented contraindication. Multivariable hierarchical relative risk regression models, including demographics, insurance status, comorbidities and a random effect for practice were used to determine 1) patient-level and 2) practice-level variation in treatment rates. To quantify practice-level variation, the median rate ratio (MRR) was calculated, which estimates the typical rate ratio between two randomly selected practices for patients with identical covariates. In general, MRRs ≥ 1.2 indicate significant variation by practice. The MRR is always &gt;1.0 but can be compared in magnitude to patient-level risks. Results: We studied 12384 patients in 45 practices. The mean practice rate for BB treatment was 87% (IQR 83%-95%; range: 43%-100%), and the mean practice rate of ACE/ARB treatment was 90% (IQR 75%-88%; range: 18%-100%). The MRR was 1.09 for BB and 1.16 for ACE/ARB therapy. For both BB and ACE/ARB, the adjusted MRR for site level variation was larger than the rate ratio for other patient factors. (Table) Conclusions: Although rates of BB and ACE/ARB treatment among outpatients with HFREF are high, clinically meaningful variation by practice is present and explains a larger amount of the observed variance than any patient characteristic. This suggests that addressing practice-level factors represents an important opportunity to improve the use of evidence-based HF therapy.

Clinical and prognostic effects of atrial fibrillation in heart failure patients with reduced and preserved left ventricular ejection fraction

Atrial fibrillation (AF) is common in heart failure (HF), but few data regarding the prognostic relevance of AF are available in HF patients with preserved left ventricular ejection fraction (HF-PEF). We aimed to study the clinical impact of AF vs. sinus rhythm (SR) in stabilized HF patients with reduced left ventricular ejection fraction (HF-REF) and in those with preserved left ventricular ejection fraction (HF-PEF). We studied 927 patients with stable HF, of whom 336 (36%) had AF. N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations were measured at baseline and patients were followed for 18 months. We compared time to first HF (re-)hospitalization or death between patients with AF and SR. Atrial fibrillation was present at baseline in 215 (35%) patients with HF-REF (mean LVEF 0.25 + 0.08) and in 121 (40%) patients with HF-PEF (mean LVEF 0.50 + 0.09). Plasma NT-proBNP levels were similar in AF and SR patients (median 2398 vs. 2532 pg/mL, P = 0.74). Atrial fibrillation was independently associated with elevated NT-proBNP levels in HF-PEF, but not in HF-REF patients (multivariable B = 0.33, P= 0.047 and B = 0.03; P = 0.89, respectively). After 18 months of follow-up, the presence of AF was an independent predictor of death or HF hospitalization in HF-PEF (multivariable hazard ratio 1.49 (95% CI 1.04-2.14), P = 0.03), but not in HF-REF patients (1.05 (CI 95% 0.80-1.38), P = 0.72). Atrial fibrillation is equally common in patients with HF-PEF and HF-REF. In HF-PEF, but not in HF-REF patients, AF was associated with higher NT-proBNP levels and was independently related to death or HF hospitalization.

Prognosis of heart failure patients with reduced and preserved ejection fraction and coexistent chronic obstructive pulmonary disease

The long-term prognosis of patients with heart failure with preserved left ventricular ejection fraction (HFPEF) and coexistent chronic obstructive pulmonary disease (COPD) has not been previously investigated. The primary aim of this study was to determine whether the long-term prognosis of HFPEF patients with COPD differs from that of heart failure patients with reduced left ventricular ejection fraction (HFREF) and COPD. The secondary aim was to identify independent predictors of event-free survival in patients with HF and COPD. We investigated 184 patients with coexistent HF and COPD. Heart failure with preserved left ventricular ejection fraction was present in 98 cases (53%) and HFREF in the remaining 86 cases (47%). Mean follow-up time was 731±369 days. Cardiovascular/pulmonary hospitalization or mortality occurred in 71 patients (39%). No significant difference was observed between the two study groups in terms of event-free survival (P=0.457), but event-free survival was found to be independently associated with New York Heart Association (NYHA) class [III vs. I, hazard ratio (HR) 2.92, 95% confidence interval (CI) 1.09-7.82], Global initiative for chronic Obstructive Lung Disease (GOLD) stage (III vs. I, HR 3.20, 95% CI 1.33-7.68), systemic hypertension (SHT; HR 2.99, 95% CI 1.41-6.33), and pulmonary hypertension (PH; HR 4.35, 95% CI 1.95-9.68). In HF patients with coexisting COPD, cardiovascular and pulmonary event-free survival of HFPEF was found to be similar to that of HFREF over 3 years follow-up. Furthermore, severe NYHA class, severe GOLD stage, SHT, and PH were found to be independent predictors of event-free survival.