Heart Failure Patients With Preserved Ejection Fraction Patients Research Articles

Beta-blocker Therapy at Discharge in Patients with Acute Heart Failure and Atrial Fibrillation.

Backgroundβ-blockers (BBs) are considered primary therapy in stable heart failure (HF) with reduced ejection fraction (HFrEF) without atrial fibrillation (AF); evidence-based benefits of BB on outcome have been documented. However, BBs have not been shown to improve mortality or reduce hospital admissions in HF patients with AF. This study assessed the relationship between BBs at discharge and relevant clinical outcomes in acute heart failure (AHF) patients with AF.MethodsFrom the Korean Acute Heart Failure Registry, 936 HFrEF and 639 HF patients with preserved ejection fraction (HFpEF) and AF were selected. Propensity score (PS) matching accounted for BB selection bias when assessing associations.ResultsBB-untreated patients in the overall cohort of HFrEF and HFpEF had greater deteriorated clinical and laboratory characteristics. In the 670 PS-matched cohort of HFrEF patients, incidences of all clinical events at 60 days and 1 year were not different according to use of BBs. In the 470 PS-matched cohort of HFpEF, rehospitalization and composite outcome at 6 months and 1 year more frequently occurred in non-users of BBs. After adjusting for covariates in the multivariable Cox model of matched cohorts, BB was not associated with clinical outcomes at 60 days and 1 year in HFrEF with AF patients. In HFpEF patients with AF, BB use was associated with reduced 6-month (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.20–0.74) and 1-year rehospitalization (HR, 0.53; 95% CI, 0.34–0.82).ConclusionIn the HFrEF with AF PS-matched cohort, the use of BBs at discharge was not associated with clinical outcome. However, in HFpEF with AF, the use of BB was associated with reduced rehospitalization during the 6-month and 1-year follow up.

A new algorithm for optimization of rate-adaptive pacing improves exercise tolerance in patients with HFpEF.

To develop an algorithm for optimization of rate-adaptive pacing settings in heart failure patients with preserved ejection fraction (HFpEF) and permanent cardiac pacing. This is a prospective randomized controlled study. A total of 54 patients with HFpEF, permanent atrial fibrillation (AF), and VVIR pacing were randomized to an intervention group with optimization of rate-adaptation parameters by using cardiopulmonary exercise testing (CPET) and pacemaker stress echocardiography (PASE), and to a control group with conventional programming. CPET, 6-min walk test (6-mwt), echocardiography (echo), Duke Activity Status Index (DASI), and Minnesota questionnaire (MLHFQ) were performed at baseline and after 3 months. PASE was used to exclude exercise-induced ischemia and to determine safe upper sensor rate. Pacing parameters were corrected to achieve optimal heart rate increments of 3-6bpm for 1mL/min/kg of VO2 (oxygen uptake). After 3 months, the intervention group demonstrated significant improvement of VO2 peak by 1.64±1.6mL/min/kg, anaerobic threshold by 1.33±1.3mL/min/kg, exercise time by 170±98s, 6-mwt distance by 75±63m (P<.0001 for all), DASI by 5.23 points (P=.009), MLHFQ-score (reduction by 9 points, P<.0001), and echo parameters (decrease in LA volume from 108 (84; 132) to 95 (85; 130) mL, P=.026; E/e' from 11.7±3.2 to 10.4±2.9, P=.025; systolic pulmonary artery pressure (SPAP) from 44±14 to 39±12mm Hg, P= .001) compared to the control group. An algorithm incorporating CPET and PASE for optimal programming of rate-adaptation parameters is a valuable tool to improve exercise capacity in HFpEF patients with permanent AF and VVIR pacing who remain exercise intolerant after conventional programming.

Prognostic value of N-terminal B-type natriuretic peptide on all-cause mortality in heart failure patients with preserved ejection fraction

Objective: To investigate the prognostic value of N-terminal B-type natriuretic peptide (NT-proBNP) on all-cause mortality in heart failure patients with preserved ejection fraction (HFpEF) at real world scenarios. Methods: Patients who met the diagnostic criteria of HFpEF in the China National Heart Failure Registration Study (CN-HF) were divided into death and survival groups. The demographic data, physical examination, results of the first echocardiography, laboratory results at admission, complications, drug use and clinical outcomes were obtained from CN-HF. The univariate Cox proportional hazard model was used to screen the variates that might predict prognosis, and then the covariates with statistical significance were included in the multivariate Cox regression model to analyze the predictive value of baseline NT-proBNP on all-cause death. Spearman correlation analysis was used to evaluate the relationship between NT-proBNP and estimated glomerular filtration rate (eGFR), so as to further explore the predictive value of the interaction between renal dysfunction and NT-proBNP on death. Since NT-proBNP did not obey the binary normal distribution, it was expressed by the natural logarithm of NT-proBNP (LnNT-proBNP). Results: A total of 1 846 HFpEF patients were enrolled in this study, with an average age of 71.5 years, 1 017 males(55.1%), median NT-proBNP 860 ng/L, and median eGFR 73.9 ml·min-1·1.73m-2. After a median follow-up of 34 months, 213 (11.5%) patients died. Patients in the death group were older, with higher NYHA classification Ⅲ-Ⅳ ratio, longer hospital stay, higher serum potassium and NT-proBNP level, prevalence of complications of diabetes mellitus, arrhythmia and atrial fibrillation, use of angiotensin receptor antagonist(ARB), mineralocorticoid receptor antagonists (MRA), diuretic and digoxin was significantly higher in death group than in survival group. Body mass index (BMI), diastolic blood pressure, left ventricular ejection fraction (LVEF), hemoglobin, serum cholesterol(TC), serum triglycerides (TG) and eGFR, and use of angiotensin converting enzyme inhibitors (ACEI), statins and aspirin were lower in death group than in survival group. Univariate Cox regression analysis showed that NT-proBNP was a predictor of all-cause death in HFpEF patients (HR=2.522, 95%CI 2.040-3.119, P<0.001). Multivariate Cox regression analysis showed that the elevated NT-proBNP remains as the independent predictor of all-cause death in patients with HFpEF (HR=1.230, 95%CI 1.049-1.442, P=0.011) after adjusting for age, BMI, diastolic blood pressure, LVEF, hemoglobin, serum potassium, serum sodium, TC, serum high-density lipoprotein cholesterol (HDL-C), TG, eGFR, atrial fibrillation, as well as the treatment of ACEI/ARB, MRA, diuretics and digoxin. Spearman correlation analysis showed that LnNT-proBNP was negatively correlated with eGFR (r=-0.361, P<0.001), but there was no interaction between NT-proBNP and renal dysfunction in predicting death in HFpEF patients (P>0.05). Conclusion: The elevated level of NT-proBNP at admission is an independent predictor of all-cause mortality in HFpEF patients.

Hypovolemia and reduced hemoglobin mass in patients with heart failure and preserved ejection fraction.

A fundamental tenet of heart failure (HF) pathophysiology hinges on a propensity for fluid retention leading to blood volume (BV) expansion and hemodilution. Whether this can be applied to heart failure patients with preserved ejection fraction (HFpEF) remains uncertain. The present study sought to determine BV status and key hormones regulating fluid homeostasis and erythropoiesis in HFpEF patients. BV and hemoglobin mass (Hbmass) were determined with high‐precision, automated carbon monoxide (CO) rebreathing in 20 stable HFpEF patients (71.5 ± 7.3 years, left ventricular ejection fraction = 55.7 ± 4.0%) and 15 healthy age‐ and sex‐matched control individuals. Additional measurements comprised key circulating BV‐regulating hormones such as pro‐atrial natriuretic peptide (proANP), copeptin, aldosterone and erythropoietin (EPO), as well as central hemodynamics and arterial stiffness via carotid–femoral pulse wave velocity (PWV). Carotid–femoral PWV was increased (+20%) in HFpEF patients versus control individuals. With respect to hematological variables, plasma volume (PV) did not differ between groups, whereas BV was decreased (−14%) in HFpEF patients. In consonance with the hypovolemic status, Hbmass was reduced (−27%) in HFpEF patients, despite they presented more than a twofold elevation of circulating EPO (+119%). Plasma concentrations of BV‐regulating hormones, including proANP (+106%), copeptin (+99%), and aldosterone (+62%), were substantially augmented in HFpEF patients. HFpEF patients may present with hypovolemia and markedly reduced Hbmass, underpinned by a generalized overactivation of endocrine systems regulating fluid homeostasis and erythropoiesis. These findings provide a novel perspective on the pathophysiological basis of the HFpEF condition.

P2601Trans-catheter or surgical mitral valve procedure versus conservative treatment in heart failure patients with preserved ejection fraction

Abstract Background Secondary mitral regurgitation (SMR) impacts outcomes in heart failure with reduced ejection fraction (HFrEF) but whether it is a specific therapeutic target in heart failure patients with preserved ejection fraction (HFpEF) is less clear. Purpose The aims of this study were to investigate whether surgical or trans-catheter intervention reduces SMR and improves outcomes compared to optimal medical therapy in HFpEF patients. Methods We retrospectively identified 120 HFpEF patients with moderate-to-severe or greater SMR from January 1, 2007, until December 31, 2017. Moderate-to-severe SMR was defined as an effective regurgitant orifice area of &gt;0.3cm2, and/or a regurgitation volume of &gt;45ml per beat. Those with primary mitral regurgitation, endocarditis, HFrEF, hypertrophic cardiomyopathy, congenital heart disease, and history of valve intervention were excluded. All-cause mortality was analyzed and correlated to clinical and echocardiographic characteristics. Amongst the 120 patients, 36 received surgical or trans-catheter procedure in addition to medical therapy (procedure group) and 84 patients received optimal medical therapy only (conservative treatment group). The median follow-up period was 864 (15–3553) days. Results Patients in the procedure group were younger (75±8 vs 81±10, P=0.0002) and with fewer comorbidities (Charlson Comorbidity Index 7.0±2.4 vs 8.0±2.0, P=0.022) compared to the conservative treatment group. In addition, the procedure group had larger left ventricular end-diastolic diameters and higher SMR volume at baseline. During follow-up, SMR decreased by ≥2 grades in 75% of patients (27/36) in the procedure group compared to 20% of patients (12/60) in the conservative treatment group. After adjusting for age and comorbidities, the procedure group showed better overall survival compared to the conservative treatment group (HR 0.37; 95% CI 0.17–0.80; P=0.011). On multivariate analysis for the different groups (procedure group vs. conservative treatment group) (HR 0.40; 95% CI 0.17–0.91; P=0.019), increasing Charlson Comorbidity Index (HR 1.16; 95% CI 1.02–1.32; P=0.028) and average mitral E/e' ratio (HR 1.06; 95% CI 1.01–1.11; P=0.031) were independent predictors of increased all-cause mortality. Kaplan-Meier Survival Curve Conclusion Among heart failure patients with preserved ejection fraction and moderate-to-severe or severe SMR, surgical or trans-catheter mitral-valve repair or replacement resulted in lower all-cause mortality compared to conservative treatment after 9 years of follow-up.

Evaluation of elevated left ventricular end diastolic pressure in patients with preserved ejection fraction using cardiac magnetic resonance.

This study aims to validate the reliability of cardiac magnetic resonance (CMR) parameters for estimating left ventricular end diastolic pressure (LVEDP) in heart failure patients with preserved ejection fraction (HFpEF) and compare their accuracy to conventional echocardiographic ones, with reference to left heart catheterisation. Sixty patients with exertional dyspnoea (New York Heart Association function class II to III) were consecutively enrolled. CMR-derived time-volume curve and deformation parameters, conventional echocardiographic diastolic indices as well as LVEDP evaluated by left heart catheterisation were collected and analysed. Fifty-one patients, who accomplished all three examinations, were divided into HFpEF group and non-HFpEF group based on LVEDP measurements. Compared to the non-HFpEF group, CMR-derived time-volume curve showed lower peak filling rate adjusted for end diastolic volume (PFR/EDV, p = 0.027), longer time to peak filling rate (T-PFR, p < 0.001), and increased T-PFR in one cardiac cycle (%T-PFR, p < 0.001) in HFpEF group. In multivariable linear regression analysis, %T-PFR (β = 0.372, p = 0.024), left ventricular global peak longitudinal diastolic strain rate (LDSR, β = -0.471, p = 0.006), and E/e' (β = 0.547, p = 0.001) were independently associated with invasively measured LVEDP. The sensitivity and specificity of E/e' and LDSR for predicting the elevated LVEDP were 76%, 92% and 76%, 89%, respectively. These findings suggest that CMR-derived time-volume curve and strain indices could predict HFpEF patients. Not only E/e' assessed by echocardiography but also the CMR-derived %T-PFR and LDSR correlated well with LVEDP. These non-invasive parameters were validated to evaluate the left ventricular diastolic function. • The abnormal time-volume curve revealed insufficient early diastole in HFpEF patients. • Non-invasive parameters including E/e', %T-PFR, and LDSR correlated well with LVEDP.

Ferritin and Prognosis in Elderly Patients with Heart Failure and Preserved Ejection Fraction

Background: Iron deficiency (ID) and anaemia are frequent in Heart Failure (HF) patients, but there are few data about its prevalence and prognosis in elderly HF patients with preserved ejection fraction (HF-PEF). Aim: The aim of this study is to ascertain if ID alone or associated with anaemia is related to negative clinical outcomes in elderly patients with HF-PEF. Design/Methods: 139 consecutive patients discharged from our Internal Medicine Department with a diagnosis of HF-PEF from June 2011 to June 2014 were followed up until June 2015. All demographic and clinical data, echocardiography, biochemical parameters, treatment at discharge, new hospital admissions and death were registered in a specific database. Results: Mean age was 79.1 years (SD 8.3 years), and 94 (67.6%) were women. Anaemia was present in 85 (61%), any iron deficiency in 92 (67%) and absolute iron deficiency in 67 (48%) of these patients. 33 patients (23%) died during a mean follow-up of 649 days. Increased mortality was related to age, previous hospital admissions, lower albumin level, lower Barthel score, and higher ferritin level. Using a composite endpoint of HF readmission or death during first year after index admission, 54 patients (38.8%) had this negative outcome. Lower Barthel Score and albumin values, higher NT pro-BNP and ferritin level, and absence of iron deficiency, were related to this negative outcome. Conclusion: Anaemia and Iron Deficiency are usual findings in our elderly HF-PEF patients, but only a high level of serum ferritin was associated with worse outcomes in this setting.

Clinical Phenotyping of Transthyretin Cardiac Amyloidosis with Bone-Seeking Radiotracers in Heart Failure with Preserved Ejection Fraction.

The two most common types of cardiac amyloidosis are caused by fibril deposits of immunoglobulin light chains (AL) and transthyretin (TTR), each with distinct prognosis and clinical management. Cardiac amyloidosis is under-recognized among heart failure patients with preserved ejection fraction (HFpEF). Bone-seeking tracers like 99mTc-PYP and 99mTc-DPD have long been used to identify cardiac amyloidosis, and more recently, to differentiate TTR from AL cardiac amyloidosis in symptomatic patients. However, results are mainly derived from single-center retrospective studies, with comparable but not standardized imaging protocols and interpretation criteria. The clinical scope of cardiac amyloidosis among HFpEF patients and current literature supporting the use of bone-seeking tracers for TTR cardiac amyloidosis are presented. The differences of imaging techniques for cardiac amyloid and bone disease evaluation, bone tracer pharmacodynamics, and imaging interpretation criteria for cardiac amyloidosis diagnosis are discussed. Finally, a diagnostic algorithm to use bone scintigraphy in cardiac amyloidosis diagnosis among HFpEF patients is proposed. Bone scintigraphy with 99mTc-PYP or 99mTc-DPD can be a useful tool with high sensitivity and specificity for detecting TTR-related cardiac amyloidosis in patients with HFpEF. It is needed to standardize the imaging protocol and interpretation criteria and to perform prospective clinical studies.

Pathological characteristics of the heart and coronary artery from elderly heart failure patients with preserved ejection fraction and coronary artery disease

Objective: To analyze the pathological feathers of the heart in elderly (60-99 years old) heart failure patients with preserved ejection fraction (HFpEF) and coronary artery disease (CAD) and to explore the misdiagnosis and missed diagnosis rates. Method: This retrospective study included 154 HFpEF (left ventricular ejection fraction (LVEF)≥50%) cases and 49 heart failure with reduced ejection fraction (HFrEF) (LVEF≤40%) cases aged 60-99 years old out of 1 485 consecutive autopsy cases. Pathological changes of the heart and coronary artery were compared between patients with HFpEF and HFrEF. The misdiagnosis and missed diagnosis rates of HFpEF were analyzed based on pathological examination. Results: Patients with HFpEF were older than those with HFrEF ((85.7±7.4) vs. (82.9±7.8) years old, P=0.017). Among all the cases, CAD was diagnosed in 105 (68.2%) HFpEF patients and 38 (77.6%) HFrEF patients. Compared with patients with HFrEF, HFpEF patients displayed less acute myocardial infarction (12.3%(19/154) vs. 59.2%(29/49), P<0.01) and more chronic myocardial ischemia (18.2%(28/154) vs. 6.1%(3/49), P=0.041). 51.9% (80/154) HFpEF and 71.4% (35/49) HFrEF patients (P=0.017) displayed >50% left anterior descending artery stenosis. Prevalence of >75% coronary arterial stenosis (51% (25/49) vs. 20.1%(31/154), P<0.001) and more than one vessel lesions (55.1%(27/49) vs. 33.8%(52/154), P=0.008) were significantly higher in HFrEF patients than in HFpEF patients. The misdiagnosis rate of CAD in HFpEF was 63.3% (31/49). Among HFpEF, the missed diagnosis rate of acute myocardial infarction was 57.9% (11/19) and the missed diagnosis rate of old myocardial infarction was 57.7% (45/78). Conclusions: CAD and chronic myocardial ischemia are common in elderly patients with HFpEF. Chronic myocardial ischemia may play an important role in the development of HFpEF of elderly CAD patients. Among HFpEF patients, the misdiagnosis rate of CAD and missed diagnosis rate of myocardial infarction are high, so the accurate evaluation of myocardial ischemia status is of great importance.

Intrarenal Flow Alterations During Transition From Euvolemia to Intravascular Volume Expansion in Heart Failure Patients

ObjectivesThe goal of this study was to assess: 1) the intrarenal flow in heart failure (HF) patients during the transition from euvolemia to intravascular volume overload; and 2) the relationship between intrarenal flow and diuretic efficiency. BackgroundIntrarenal blood flow alterations may help to better understand impaired volume handling in HF. MethodsResistance index (RI) and venous impedance index (VII) were assessed in 6 healthy subjects, 40 euvolemic HF patients with reduced ejection fraction (HFrEF), and 10 HF patients with preserved ejection fraction (HFpEF). Assessments were performed by using Doppler ultrasonography at baseline, during 3 h of intravascular volume expansion with 1 l of hydroxyethyl starch 6%, and 1 h after the administration of a loop diuretic. Clinical parameters, echocardiography, and biochemistry were assessed. Urine output was collected after 3 and 24 h. ResultsIn response to volume expansion, VII increased significantly in HFrEF patients (0.4 ± 0.3 to 0.7 ± 0.2; p < 0.001) and in HFpEF patients (0.4 ± 0.3 to 0.7 ± 0.2; p = 0.002) but not in healthy subjects (0.2 ± 0.2 to 0.3 ± 0.1; p = 0.622). This outcome was reversed after loop diuretic administration. In contrast, RI did not change significantly after volume expansion. Echocardiographic-estimated filling pressures did not change significantly. VII during volume expansion was significantly correlated with diuretic response in HF patients independent of baseline renal function (R2 = 0.35; p < 0.001). ConclusionsIn HF patients, intravascular volume expansion resulted in significant blunting of venous flow before a significant increase in cardiac filling pressures could be demonstrated. The observed impaired renal venous flow is correlated with less diuretic efficiency. Intrarenal venous flow patterns may be of interest for evaluating renal congestion.

Effects of supervised exercise and dietary nitrate in older adults with controlled hypertension and/or heart failure with preserved ejection fraction

Aerobic exercise training is an effective therapy to improve peak aerobic power (peak VO2) in individuals with hypertension (HTN, AHA/ACC class A) and heart failure patients with preserved ejection fraction (HFpEF). High nitrate containing beetroot juice (BRJ) also improves sub-maximal endurance and decreases blood pressure in both HTN and HFpEF. We hypothesized that combining an aerobic exercise and dietary nitrate intervention would result in additive or even synergistic positive effects on exercise tolerance and blood pressure in HTN or HFpEF. We report results from two pilot studies examining the effects of supervised aerobic exercise combined with dietary nitrate in patients with controlled HTN (n = 26, average age 65 ± 5 years) and in patients with HFpEF (n = 20, average age 69 ± 7 years). All patients underwent an aerobic exercise training regimen; half were randomly assigned to consume a high nitrate-containing beet juice beverage (BRJ containing 6.1 mmol nitrate for the HFpEF study consumed three times a week and 8 mmol nitrate for the HTN study consumed daily) while the other half consumed a beet juice beverage with the nitrate removed (placebo). The main result was that there was no added benefit observed for any outcomes when comparing BRJ to placebo in either HTN or HFpEF patients undergoing exercise training (p ≥ 0.14). There were within-group benefits. In the pilot study in patients with HFpEF, aerobic endurance (primary outcome), defined as the exercise time to volitional exhaustion during submaximal cycling at 75% of maximal power output, improved during exercise training within each group from baseline to end of study, 369 ± 149 s vs 520 ± 257 s (p = 0.04) for the placebo group and 384 ± 129 s vs 483 ± 258 s for the BRJ group (p = 0.15). Resting systolic blood pressure in patients with HFpEF also improved during exercise training in both groups, 136 ± 16 mm Hg vs 122 ± 3 mm Hg for the placebo group (p < 0.05) and 132 ± 12 mm Hg vs 119 ± 9 mm Hg for the BRJ group (p < 0.05). In the HTN pilot study, during a treadmill graded exercise test, peak oxygen consumption (primary outcome) did not change significantly, but time to exhaustion (also a primary outcome) improved in both groups, 504 ± 32 s vs 601 ± 38 s (p < 0.05) for the placebo group and 690 ± 38 s vs 772 ± 95 s for the BRJ group (p < 0.05) which was associated with a reduction in supine resting systolic blood pressure in BRJ group. Arterial compliance also improved during aerobic exercise training in both the HFpEF and the HTN patients for both BRJ and placebo groups. Future work is needed to determine if larger nitrate doses would provide an added benefit to supervised aerobic exercise in HTN and HFpEF patients.

Evidence of an Exaggerated Muscle Metaboreflex Response in Heart Failure with Preserved Ejection Fraction

BackgroundExercise intolerance is the primary chronic symptom in heart failure patients with preserved ejection fraction (HFpEF), and often persists even with optimized treatment. Though there are many mechanisms that may contribute to this deficit, disease‐related changes in the muscle metaboreflex may play a role. Indeed, it has been previously shown that in heart failure with reduced ejection fraction (HFrEF), input from group III/IV muscle afferents contributes to the development of fatigue and exercise intolerance. Therefore, the purpose of this study was to examine metaboreflex modulation of heart rate (HR) and mean arterial pressure (MAP) in HFpEF patients.MethodsEight HFpEF patients (6M, 2F; age 67 ± 4 yrs; BMI 35 ± 3 kg/m2; ejection fraction 63 ± 3%) and seven healthy controls (4M, 3F; age 59 ± 3 yrs; BMI 30 ± 1 kg/m2) participated in this study. Patients were studied under their normal pharmacotherapy. After 30 min of supine rest, participants performed 2 min of isometric handgrip exercise at 30% and 40% of maximal voluntary contraction (MVC), followed by 2 min of post‐exercise circulatory occlusion (PECO) to isolate the muscle metaboreflex response. HR (3‐lead ECG) and arterial blood pressure (Finapres Medical Systems BV) were measured continuously, and the last 30 sec of exercise and PECO was averaged to determine peak changes in HR and MAP.ResultsBaseline HR and MAP were not different between HFpEF and controls (70 ± 7 vs. 68 ± 5 bpm; 97 ± 4 vs. 103 ± 5 mmHg, respectively). At 30% MVC, comparable ΔHR were observed between groups during handgrip (6 ± 1 vs. 4 ± 2 bpm, HFpEF vs. control) and PECO (2 ± 1 vs. 2 ± 1 bpm, HFpEF vs. control). While ΔMAP was similar between groups during handgrip (15 ± 2 vs. 14 ± 3 mmHg, HFpEF vs. control), HFpEF patients exhibited a greater ΔMAP during PECO (16 ± 2 vs. 8 ± 3 mmHg, HFpEF vs. control, p&lt;0.05). At 40% MVC, ΔHR was not significantly different between HFpEF and controls during handgrip (7 ± 3 vs. 12 ± 2 bpm, respectively) or PECO (1 ± 1 vs. 1 ± 2 bpm, respectively). Similarly, ΔMAP at 40% MVC was comparable between the groups during handgrip (24 ± 5 vs. 24 ± 2 mmHg, HFpEF vs. control), whereas there was a trend towards a greater ΔMAP during PECO in the HFpEF patients (24 ± 5 vs. 16 ± 3 mmHg, p=0.16).ConclusionsWhile the overall pressor response during handgrip was comparable between groups, a notable elevation in blood pressure was observed during PECO in the HFpEF patients. It is important to note that these differences occurred with the patients maintaining their normal pharmacotherapy, which often includes antihypertensive agents. These preliminary findings suggest that the muscle metaboreflex is exaggerated in patients with HFpEF, and this may be involved in the exercise intolerance observed in this patient population.Support or Funding InformationFunded in part by the National Institutes of Health (HL118313) and the U.S. Department of Veterans Affairs (RX001697, RX001418, E6910R)

Highlights from the Circulation Family of Journals.

Highlights from the Circulation Family of Journals.

The anti-ageing molecule sirt1 mediates beneficial effects of cardiac rehabilitation

BackgroundAn exercise-based Cardiac Rehabilitation Programme (CRP) is established as adjuvant therapy in heart failure (HF), nevertheless it is underutilized, especially in the elderly. While the functional and hemodynamic effects of CRP are well known, its underlying molecular mechanisms have not been fully clarified. The present study aims to evaluate the effects of a well-structured 4-week CRP in patients with stable HF from a molecular point of view.ResultsA prospective longitudinal observational study was conducted on patients consecutively admitted to cardiac rehabilitation. In fifty elderly HF patients with preserved ejection fraction (HFpEF), levels of sirtuin 1 (Sirt1) in peripheral blood mononuclear cells (PBMCs) and of its targets, the antioxidants catalase (Cat) and superoxide dismutase (SOD) in serum were measured before (Patients, P) and at the end of the CRP (Rehabilitated Patients, RP), showing a rise of their activities after rehabilitation.Endothelial cells (ECs) were conditioned with serum from P and RP, and oxidative stress was induced using hydrogen peroxide. An increase of Sirt1 and Cat activity was detected in RP-conditioned ECs in both the absence and presence of oxidative stress, together with a decrease of senescence, an effect not observed during Sirt1 and Cat inhibition.ConclusionsIn addition to the improvement in functional and hemodynamic parameters, a supervised exercise-based CRP increases Sirt1 activity and stimulates a systemic antioxidant defence in elderly HFpEF patients. Moreover, CRP produces antioxidant and anti-senescent effects in human endothelial cells mediated, at least in part, by Sirt1 and its target Cat.

Renin-Angiotensin System Inhibition, Worsening Renal Function, and Outcome in Heart Failure Patients With Reduced and Preserved Ejection Fraction: A Meta-Analysis of Published Study Data.

Renin-angiotensin aldosterone system (RAAS) inhibitors significantly improve outcome in heart failure (HF) patients with reduced ejection fraction (HFREF), irrespective of the occurrence of worsening renal function (WRF). However, in HF patients with preserved ejection fraction (HFPEF), RAAS inhibitors have not been shown to improve outcome but are still frequently prescribed. Random effect meta-analysis was performed to investigate the relationship between RAAS inhibitor therapy, WRF in both HF phenotypes, and mortality. Studies were selected based on literature search in MEDLNE and included randomized, placebo controlled trials of RAAS inhibitors in chronic HF. The primary outcome consisted of the interaction analysis for the association between RAAS inhibition-induced WRF, HF phenotype and outcome. A total of 8 studies (6 HFREF and 2 HFPEF, including 28 961 patients) were included in our analysis. WRF was more frequent in the RAAS inhibitor group, compared with the placebo group, in both HFREF and HFPEF. In HFREF, WRF induced by RAAS inhibitor therapy was associated with a less increased relative risk of mortality (relative risk, 1.19 (1.08-1.31); P<0.001), compared with WRF induced by placebo (relative risk, 1.48 (1.35-1.62); P<0.001; P for interaction 0.005). In contrast, WRF induced by RAAS inhibitor therapy was strongly associated with worse outcomes in HFPEF (relative risk, 1.78 (1.43-2.21); P<0.001), whereas placebo-induced WRF was not (relative risk, 1.25 (0.88-1.77); P=0.21; P for interaction 0.002). RAAS inhibitors induce renal dysfunction in both HFREF and HFPEF. However, in contrast to patients with HFREF where mortality increase with WRF is small, HFPEF patients with RAAS inhibitor-induced WRF have an increased mortality risk, without experiencing improved outcome with RAAS inhibition.

Impaired skeletal muscle vasodilation during exercise in heart failure with preserved ejection fraction

BackgroundExercise intolerance is a hallmark symptom of heart failure patients with preserved ejection fraction (HFpEF), which may be related to an impaired ability to appropriately increase blood flow to the exercising muscle. MethodsWe evaluated leg blood flow (LBF, ultrasound Doppler), heart rate (HR), stroke volume (SV), cardiac output (CO), and mean arterial blood pressure (MAP, photoplethysmography) during dynamic, single leg knee-extensor (KE) exercise in HFpEF patients (n=21; 68±2yrs) and healthy controls (n=20; 71±2yrs). ResultsHFpEF patients exhibited a marked attrition during KE exercise, with only 60% able to complete the exercise protocol. In participants who completed all exercise intensities (0–5–10–15W; HFpEF, n=13; Controls, n=16), LBF was not different at 0W and 5W, but was 15–25% lower in HFpEF compared to controls at 10W and 15W (P<0.001). Likewise, leg vascular conductance (LVC), an index of vasodilation, was not different at 0W and 5W, but was 15–20% lower in HFpEF compared to controls at 10W and 15W (P<0.05). In contrast to these peripheral deficits, exercise-induced changes in central variables (HR, SV, CO), as well as MAP, were similar between groups. ConclusionsThese data reveal a marked reduction in LBF and LVC in HFpEF patients during exercise that cannot be attributed to a disease-related alteration in central hemodynamics, suggesting that impaired vasodilation in the exercising skeletal muscle vasculature may play a key role in the exercise intolerance associated with this patient population.

Diagnostic values of mitral inflow and mitral annulus diastolic velocity for heart failure with preserved ejection fraction

To explore the diagnostic values of ratios of early diastolic peak transmitral velocity(E) to late velocity(A) (E/A) and E to early diastolic peak mitral annulus velocity (E/E') for heart failure patients with preserved ejection fraction (HF-PEF). Two hundred and sixteen healthy people were divided into <50 years, 50-59 years, 60-69 years, and ≥70 years groups to clarify the impact of aging on E/A and E/E'. Two hundred and two newly diagnosed consecutive in-patients with HF-PEF and 221 age- and sex-matched non-heart-failure subjects with risk factors of HF-PEF (negative controls) were enrolled.The diagnostic values and cutoff points of E/A and E/E' for HF-PEF were derived from receiver operating characteristic curve (ROC) analysis. E/A and E/E' were significantly different among age groups in healthy controls (all P<0.01). Compared with <50 years group, average E/A was lower and average E/E' was higher in ≥70 years group(both P<0.01). E/A ratio was less than 1 in 68%(71/105), E/E' was >8 cm/s in 48% (50/105)healthy people with age≥60 years. Neither E/A nor E/E' of HF-PEF patients was statistically different regarding to NYHA classification (grade Ⅱ, Ⅲ, Ⅳ), but NT-proBNP value increased in proportion to higher NYHA classification(P<0.01). The area of E/E' under ROC for diagnosing HF-PEF was 0.839(P<0.01), and the corresponding cutoff point was 9.5 with a sensitivity of 86% and a specificity of 69%. The areas of E/A (larger value or smaller value indicating positive) under ROC for diagnosing HF-PEF were 0.469 and 0.531, respectively(all P>0.05). Aging exerts significant impacts on both E/A and E/E'. E/E' has moderate diagnostic accuracy while E/A is of limited value for diagnosing HF-PEF.

Prognostic value of plasma galectin-3 levels in patients with coronary heart disease and chronic heart failure.

In this study, we evaluated the prognostic value of plasma galectin-3 levels in patients with coronary heart disease (CHD) and chronic heart failure (HF) and selected 261 CHD patients who were consecutively admitted to our hospital. The enrolled chronic HF patients included HF patients with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). Patients without HF served as the control group. Galectin-3 and B-type natriuretic peptide (BNP) levels were determined and the primary endpoint was the composite of all-cause mortality and rehospitalization with 12-month follow-up. Plasma galectin-3 levels were higher in HF patients compared with non-HF patients (P < 0.001). Receiver operating characteristic (ROC) analyses for diagnosis of HF showed that galectin-3 had the greatest area under the curve (AUC) of 0.756 (P < 0.001), with an optimal cutoff of 10.8 ng/mL, yielding a sensitivity of 81.7% and a specificity of 61.7%. Follow-up ROC analyses of galectin-3 for outcome prediction showed an optimal cutoff of 17.8 ng/ mL, yielding a sensitivity of 97.3% and a specificity of 77.6%. Galectin-3 yielded an AUC of 0.899 (P < 0.001), whereas the AUC of BNP was 0.633 (P = 0.022). Galectin-3 led to an AUC of 0.931 (P < 0.001) for HFpEF and an AUC of 0.882 (P < 0.001) for HFrEF. Cox proportional hazards regression analysis revealed that galectin-3 was an independent prognostic predictor for chronic HF, especially for HFpEF patients (RR: 1.231, 95% CI: 1.066-1.442). In summary, plasma galectin-3 levels were increased in CHD HF patients and were an independent predictor of all-cause mortality and rehospitalization. In HFpEF patients galectin-3 levels correlated stronger with outcomes than in HFrEF patients.

Evidence of impaired vasodilation during exercise in heart failure with preserved ejection fraction (1156.3)

Exercise intolerance is a hallmark characteristic of heart failure (HF), which may be related to impaired exercise‐induced vasodilation in the exercising muscle vasculature. While reductions in exercising limb blood flow have been observed in patients with systolic HF no studies, to date, have evaluated vasodilation in HF patients with preserved ejection fraction (HFpEF) during exercise. Thus, in six HFpEF patients (68±8 yrs) and six age‐ and sex‐matched controls (69±9 yrs), arterial pressure (Finapres) and leg blood flow (LBF; ultrasound Doppler) were assessed during knee‐extension exercise at 0, 5, 10, and 15 W. Resting arterial pressure (HFpEF: 98±2 mmHg; controls: 105±16 mmHg) and LBF (HFpEF: 276±57 mL/min; controls: 299±59 mL/min) were similar between groups. Across work rates, arterial pressure was similar between groups, yet LBF was 30‐40% lower in HFpEF compared to controls (1,256±219 vs. 1,791±151, 1,420±206 vs. 2,102±179, 1,666±91 vs. 2,459±417, and 1,745±206 vs. 2,874±206 mL/min, HFpEF vs. controls at 0, 5, 10, and 15 W, respectively). These data indicate that exercise‐induced vasodilation is markedly impaired in HFpEF patients, which likely contributes to exercise intolerance in this patient population.Grant Funding Source: Supported by NIH PO1 HL‐091830 (R.S.R.) VA RR&amp;D E6910R (R.S.R.) AHA 0835209N (D.W.W)

Peripheral vascular function in heart failure patients with preserved ejection fraction (1156.4)

While peripheral vascular dysfunction is well‐described in heart failure patients with reduced ejection fraction, disease‐related changes in vascular function in heart failure patients with preserved ejection fraction (HFpEF) remains unclear. Thus, in six HFpEF patients (73 ± 4 yrs) and six healthy controls matched for age (74 ± 4 yrs), sex, and brachial artery (BA) diameter, ultrasound Doppler was utilized to determine BA flow‐mediated vasodilation (FMD) and reactive hyperemia (RH) following 5 minutes of suprasystolic cuff occlusion. BA FMD was lower in HFpEF patients (3.9 ± 0.9 %) compared to controls (6.0 ± 1.0 %). Likewise, the RH response, calculated as the cumulative BA blood flow (area under the curve), was reduced by ~50% in patients with HFpEF compared to controls (385 ± 56 vs. 698 ± 104 ml, HFpEF vs. controls). These results indicate a clear impairment in peripheral vascular function in patients with HFpEF beyond that observed with healthy aging, providing new insight into the pathophysiology of this understudied disease.Grant Funding Source: Supported by NIH PO1 HL‐091830, VA RR&amp;D E6910R, and AHA 0835209N.