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2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines
- Paul A. Heidenreich,
- Biykem Bozkurt,
- David Aguilar,
- Larry A. Allen,
- Joni J. Byun,
- Monica M. Colvin,
- Anita Deswal,
- Mark H. Drazner,
- Shannon M. Dunlay,
- Linda R. Evers,
- James C. Fang,
- Savitri E. Fedson,
- Gregg C. Fonarow,
- Salim S. Hayek,
- Adrian F. Hernandez,
- Prateeti Khazanie,
- Michelle M. Kittleson,
- Christopher S. Lee,
- Mark S. Link,
- Carmelo A. Milano,
- Lorraine C. Nnacheta,
- Alexander T. Sandhu,
- Lynne Warner Stevenson,
- Orly Vardeny,
- Amanda R. Vest and
- Clyde W. Yancy
Circulation Volume 145, Issue 183 May 2022

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Aim:The “2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure” replaces the “2013 ACCF/AHA Guideline for the Management of Heart Failure” and the “2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure.” The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with heart failure.Methods:A comprehensive literature search was conducted from May 2020 to December 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from MEDLINE (PubMed), EMBASE, the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and other relevant databases. Additional relevant clinical trials and research studies, published through September 2021, were also considered. This guideline was harmonized with other American Heart Association/American College of Cardiology guidelines published through December 2021.Structure:Heart failure remains a leading cause of morbidity and mortality globally. The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients’ interests. Many recommendations from the earlier heart failure guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. Value statements are provided for certain treatments with high-quality published economic analyses.
2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines
- Paul A. Heidenreich,
- Biykem Bozkurt,
- David Aguilar,
- Larry A. Allen,
- Joni J. Byun,
- Monica M. Colvin,
- Anita Deswal,
- Mark H. Drazner,
- Shannon M. Dunlay,
- Linda R. Evers,
- James C. Fang,
- Savitri E. Fedson,
- Gregg C. Fonarow,
- Salim S. Hayek,
- Adrian F. Hernandez,
- Prateeti Khazanie,
- Michelle M. Kittleson,
- Christopher S. Lee,
- Mark S. Link,
- Carmelo A. Milano,
- Lorraine C. Nnacheta,
- Alexander T. Sandhu,
- Lynne Warner Stevenson,
- Orly Vardeny,
- Amanda R. Vest and
- Clyde W. Yancy
Circulation Volume 145, Issue 183 May 2022

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Aim:The “2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure” replaces the “2013 ACCF/AHA Guideline for the Management of Heart Failure” and the “2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure.” The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with heart failure.Methods:A comprehensive literature search was conducted from May 2020 to December 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from MEDLINE (PubMed), EMBASE, the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and other relevant databases. Additional relevant clinical trials and research studies, published through September 2021, were also considered. This guideline was harmonized with other American Heart Association/American College of Cardiology guidelines published through December 2021.Structure:Heart failure remains a leading cause of morbidity and mortality globally. The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients’ interests. Many recommendations from the earlier heart failure guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. Value statements are provided for certain treatments with high-quality published economic analyses.
Abstract 15264: Clinical Outcomes and Cardiovascular Responses to Exercise Training in Heart Failure Patients with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis
- Gudrun Dieberg,
- Hashbullah Ismail,
- Francesco Giallauria and
- Neil A Smart
Circulation Volume 130, Issue suppl_225 November 2014

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Background: Exercise training induces physical adaptations for heart failure patients with systolic dysfunction but less is known about those patients with preserved ejection fraction.Objectives: To establish if exercise training produces changes in peak VO₂ and related measures, quality of life, general health and diastolic function in heart failure patients with preserved ejection fraction (HFpEF).Methods: We conducted a MEDLINE search (1985 to March 2014), for exercise based rehabilitation trials in heart failure, using search terms ‘exercise training, heart failure with preserved ejection fraction, heart failure with normal ejection fraction, peak VO₂ and diastolic heart dysfunction’. Seven intervention studies were included providing a total of 144 exercising subjects and 114 control subjects, a total of 258 participants.Results: Peak VO₂ increased by a mean difference (MD) 2.13 ml.kg^-1.min^-1 (95% C.I. 1.54 to 2.71, p<0.00001) in exercise training versus sedentary control, equating to a 17% improvement from baseline. The corresponding data for V_E/VCO₂ slope MD 0.85 ml.kg^-1.min^-1 (95% C.I. 0.05 to 1.65, p=0.04); maximum heart rate MD 5.60 bpm (95% C.I. 3.95 to 7.25, p<0.00001); and 6 Minute Walk Test (6MWT) MD 32.1m (95% C.I. 17.2 to 47.1, p<0.0001); diastolic function; E/A ratio MD 0.07 (95% C.I. 0.02 to 0.12, p=0.005); E/E’ ratio MD -2.31 (95% C.I. -3.44 to -1.19, p<0.0001); Deceleration time (D_T) MD -13.2 msec (95% C.I. -19.8 to -6.5, p=0.0001); Minnesota Living with Heart Failure Questionnaire (MLHFQ) MD -6.50 (95% C.I. -9.47 to -3.53, p<0.0001); Short Form (36) Health Survey MD 15.6 (95% C.I. 7.4 to 23.8, p=0.0002). In 3,744 hours patient-hours of training, not one death was directly attributable to exercise.Conclusions: Exercise training appears to effect several health-related improvements in people with heart failure and preserved ejection fraction.
Abstract 11141: Left Ventricular Global Longitudinal Strain in Patients With Heart Failure With Preserved Ejection Fraction: Outcomes Following an Acute Heart Failure Hospitalization
- Jonathan Buggey,
- Fawaz Alenezi,
- Hyun Ju Yoon,
- Matthew Phelan,
- Adam D DeVore,
- Michel G Khouri,
- Phillip J Schulte and
- Eric J Velazquez
Circulation Volume 132, Issue suppl_310 November 2015

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Objectives: To assess the association between abnormal left ventricular global longitudinal strain (LV GLS) and outcomes in patients hospitalized with acute heart failure with preserved ejection fraction (HFpEF).Methods: Patients discharged alive from Duke University Medical Center between 2007 and 2010 following admission for acute HFpEF who had an echocardiogram with left ventricular ejection fraction ≥50% during the admission comprised the analysis cohort. We performed 2-dimensional, speckle-tracking analysis and stratified the cohort by LV GLS as normal (≤-16%) or abnormal (>-16%). Cox proportional hazards models assessed the association between continuous LV GLS and outcomes.Results: We identified 545 consecutive patients with measurable LV GLS. The median LV GLS was -12.6% (25^th -75^th percentile, -15.5% to -10.6%) and 424 (78%) had abnormal LV GLS. Patients with abnormal LV GLS had higher levels of NT-proBNP (2548 vs. 1522 pg/mL, p=0.02) compared to those with normal LV GLS. There was no statistically significant association between LV GLS and mortality through 5 years (adjusted HR 1.02 per 1% increase; 95% CI: 0.98 to 1.06; p=0.33) or mortality and hospitalization (adjusted HR 1.02 per 1% increase; 95% CI: 0.99 to1.06; p=0.25) (Figure). A similar trend was seen between LV GLS and mortality and hospitalizations at 30 days (adjusted HR 1.08 per 1% increase; 95% CI: 1.00 to1.16; p=0.06) and 1 year (adjusted HR 1.04 per 1% increase; 95% CI: 1.00 to1.09; p=0.08).Conclusions: Using a cutoff value for LV GLS of -16%, a high prevalence of patients with acute HFpEF have abnormal LV GLS suggesting covert myocardial systolic dysfunction. However, LV GLS was not associated with mortality after accounting for traditional risk factors. Further studies are necessary to understand the role for LV GLS in routine clinical practice for HFpEF patients.
Abstract 13174: Sex Differences in Clinical Characteristics, Management and Prognosis in Patients With Heart Failure With Preserved Ejection Faction: Insights From the CHART-2 Study
- Kanako Tsuji,
- Yasuhiko Sakata,
- Masanobu Miura,
- Soichiro Tadaki,
- Ryoichi Ushigome,
- Takeshi Yamauchi,
- Kenjiro Sato,
- Takeo Onose,
- Ruri Abe,
- Kotaro Nochioka,
- Jun Takahashi,
- Satoshi Miyata and
- Hiroaki Shimokawa
Circulation Volume 132, Issue suppl_310 November 2015

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Background: The number of the patients with heart failure with preserved ejection fraction (HFpEF) has been rapidly increasing worldwide. However, sex differences in patients with HFpEF remain to be elucidated.Methods and Results: We examined sex differences in 3,124 consecutive patients with HFpEF (EF≥50%, mean 69.4years, 34.7% female) registered in our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (N=10,219). Female patients, as compared with male patients, were characterized by higher age (72 vs. 68 years, P<0.01), higher LVEF (67 vs. 64%, P<0.01), higher heart rate (74 vs. 70bpm, PNYHA class III (14.1 vs. 7.0%, P<0.01), higher BNP levels (106 vs. 73pg/mL, P<0.01), lower prevalence of coronary artery disease (30 vs. 53%, P<0.01) and lower prescription rates of renin angiotensin system inhibitors (64.7 vs. 71.8%, P<0.01) and beta-blockers (37.8 vs. 43.9%, P<0.01). During the median 3.2-year follow-up, 147 female patients and 245 males died. Although there was no sex difference in all-cause mortality (13.6 vs. 12.0%, P=0.11), female patients more frequently died due to cardiovascular causes (53.7 vs. 39.2%, hazard ratio (HR): 1.62, 95% CI 1.20-2.18, P<0.01), and experienced more HF admissions (12.6 vs. 9.8%, HR: 1.35, 95% CI 1.08-1.68, P<0.01). Use of beta-blockers or renin-angiotensin system inhibitors was not associated with decreased incidence of death or HF admission in both sexes. In contrast, use of statins was associated with reduced incidence of all-cause death in both sexes (males and females; adjusted HR, 0.59 and 0.57; 95% CI 0.46-0.77 and 0.47-0.70, respectively, both P<0.01) and was also associated with reduced incidence of HF admission in males (adjusted HR: 0.67, 95%CI 0.53-0.85, P<0.01) but not in females (adjusted HR: 0.83, 95% CI 0.63-1.10, P=0.19).Conclusions: As compared with males, female patients with HFpEF were characterized by severer condition of HF and increased risk of cardiovascular death and HF admission. Although statin use was equally associated with improved mortality in both sexes, female patients with HFpEF may benefit from statins less than males in terms of reduction of HF admission.
Abstract 15431: Impact of Malnutrition as a Key Prognostic Factor in Patients With Heart Failure With Preserved Ejection Fraction
- Tetsuya Takahashi,
- Tetsu Watanabe,
- Taro Narumi,
- Takayuki Sugai,
- Taku Toshima,
- Miyuki Yokoyama,
- Daisuke Kinoshita,
- Satoshi Nishiyama,
- Hiroki Takahashi,
- Takanori Arimoto,
- Tetsuro Shishido,
- Takuya Miyamoto and
- Isao Kubota
Circulation Volume 132, Issue suppl_310 November 2015

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Background: Malnutrition is one of the unfavorable prognostic factors in patients with heart failure (HF). Prevalence of HF with preserved ejection fraction (PEF) (defined as left ventricular ejection fraction >50%) has been increased and there is an obvious association between HF-PEF and hypertension, diabetes mellitus, and insulin resistance. However, association between malnutrition and clinical outcomes in patients with HFPEF remains to be elucidated.Methods and Results: We evaluated controlling nutritional status score (CONUT), prognostic nutritional index (PNI), and geriatric nutritional risk index (GNRI) in 190 patients with HFPEF (mean 69.9 ± 11.6 years) admitted to our hospital. Patients were prospectively followed with the endpoints being cardiovascular death or rehospitalization. There were 56 events including 14 deaths and 42 rehospitalizations during a median follow-up of 14.0 months. Patients with cardiac events showed more severe New York Heart Association (NYHA) functional class and lower left ventricular ejection fraction (LVEF) compared with those without. Total lymphocyte count, serum albumin, and total cholesterol level were lower in patients with cardiac events. Patients with cardiac events showed higher CONUT score (6 vs 2, P<0.001), lower PNI (30.4 vs 38.9, P<0.001), and lower GNRI (84.9 vs 96.3, P<0.001) compared with those who without. The correlations between each nutritional index and clinical parameters were examined. CONUT score, PNI, and GNRI correlated with age, LVEF, and serum brain natriuretic peptide (BNP) level. In Cox proportional hazards analysis, higher CONUT score (adjusted hazard ratio 9.0, 95% confidence interval (CI) 3.2-25.2), lower PNI (3.6, 1.7-7.7), and lower GNRI (6.3, 2.7-14.9) were independently associated with cardiac events after adjustment of age, gender, NYHA functional class, and serum BNP level. Kaplan-Meier analysis revealed that significantly higher cardiac event rate was observed in the patients with malnutrition (log-rank test, P<0.001).Conclusion: Malnutrition was associated with unfavorable outcomes in patients with HFPEF. Evaluating nutritional status may provide valuable prognostic information in patients with HFPEF.
Abstract 16254: Heart Rate as a Prognostic Marker in Patients With Heart Failure With Preserved Ejection Fraction
- Ozlem Bilen,
- Sarah Marks,
- Lisa M Wruck,
- Umair Khalid,
- Salim S Virani,
- Vijay Nambi,
- Hani Jneid,
- Luke Cunningham,
- Patciria Chang,
- Biykem Bozkurt and
- Anita Deswal
Circulation Volume 132, Issue suppl_310 November 2015

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Introduction: Higher heart rate is associated with worse outcomes in patients with heart failure (HF) and reduced left ventricular ejection fraction (EF). This association is less certain in patients with HF and preserved EF (HFpEF).Methods: The Atherosclerosis Risk in Communities (ARIC) HF community surveillance study sampled HF hospitalizations from 2005-2010 identified by ICD discharge codes (for patients aged ≥ 55 years from 4 US communities). Patients with validated acute decompensated HF (ADHF) and EF ≥50% were categorized as HFpEF. We examined the association between quartiles of heart rate (HRt) at admission and 1-year mortality in HFpEF patients using multivariable Cox-proportional hazard models. Patients with atrial fibrillation, pacemakers and ICDs, and patients with missing covariates were excluded. Analyses were weighted to account for the stratified sampling design.Results: The final study sample included 874 HFpEF hospitalizations (weighted n=3934). Patients with lower HRt were more often male; more often had hypertension, less lung disease, had lower eGFR values and were more often on beta-blockers and diuretics. Unadjusted Kaplan Meier curves showed significant survival differences between the HRt quartiles (Fig). After adjusting for demographics, comorbidities, labs and medications (including beta blockers), compared to patients in the lowest HRt quartile, patients with HRt in the highest quartile had the highest risk of mortality (hazard ratio [95% CI] 2.07 [1.22-3.52]); patients in the 3rd and 2nd quartiles also had elevated risks (1.92 [1.22-3.04] and 1.44 [0.90-2.23]).Conclusions: There is a strong association between increasing HRt at admission and 1-year mortality in acute decompensated HFpEF.
Development of Left Ventricular Diastolic Dysfunction With Preservation of Ejection Fraction During Progression of Infant Right Ventricular Hypertrophy
- Kazuo Kitahori,
- Huamei He,
- Mitsuhiro Kawata,
- Douglas B. Cowan,
- Ingeborg Friehs,
- Pedro J. del Nido and
- Francis X. McGowan
Circulation: Heart Failure Volume 2, Issue 61 November 2009

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Background— Progressive left ventricular (LV) dysfunction can be a major late complication in patients with chronic right ventricular pressure overload (eg, tetralogy of Fallot). Therefore, we examined LV function (serial echocardiography and ex vivo Langendorff) and histology in a model of infant pressure-load right ventricular hypertrophy (RVH).Methods and Results— Ten-day-old rabbits (n=6 per time point, total n=48) that underwent pulmonary artery banding were euthanized at 2 to 8 weeks after pulmonary artery banding, and comparisons were made with age-matched sham controls. LV performance (myocardial performance index) decreased during the progression of RVH, although the LV ejection fraction was maintained. In addition, RVH caused significant septal displacement, reduced septal contractility, and decreased LV end-systolic and end-diastolic dimensions, resulting in LV diastolic dysfunction with the appearance of preserved ejection fraction. Significant septal and LV free-wall apoptosis (myocyte-specific TUNEL and activated caspase-3), fibrosis (Masson trichrome stain), and reduced capillary density (CD31 immunostaining) occurred in the pulmonary artery banding group after 6 to 8 weeks (all P<0.05).Conclusion— This is the first study showing that pressure overload of the right ventricular resulting in RVH causes LV diastolic dysfunction while preserving ejection fraction through mechanical and molecular effects on the septum and LV myocardium. In particular, the development of RVH is associated with septal and LV apoptosis and reduced LV capillary density.
Impaired Heart Rate Recovery and Chronotropic Incompetence in Patients With Heart Failure With Preserved Ejection Fraction
- Thanh Trung Phan,
- Ganesh Nallur Shivu,
- Khalid Abozguia,
- Chris Davies,
- Mohammad Nassimizadeh,
- Donie Jimenez,
- Rebekah Weaver,
- Ibrar Ahmed and
- Michael Frenneaux
Circulation: Heart Failure Volume 3, Issue 11 January 2010

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Background— This study assessed the chronotropic response to exercise and heart rate (HR) recovery after exercise in a carefully phenotyped group of patients with heart failure with preserved left ventricular ejection fraction (HfpEF) and a control group of similar age and gender distribution.Methods and Results— We studied 41 patients with HfpEF, 41 healthy controls, and 16 hypertensive controls. None were taking HR-limiting medications. All study participants had clinical examination, 12-lead ECG, pulmonary function test, echocardiogram, and metabolic exercise test with HR monitoring throughout exercise. Chronotropic response was measured by the percentage of the HR reserve used during maximal exercise and the peak exercise HR as a percentage of predicted maximal HR. Patients with HfpEF were generally women (70%), overweight, aged 69±8 years. Controls were of similar gender (63%) and age (67±6 years). Patients with HfpEF had significantly reduced peak VO₂ compared with controls (20±4 mL · kg⁻¹ · min⁻¹ versus 31±6 mL · kg⁻¹ · min⁻¹, P<0.001) and greater minute ventilation-carbon dioxide production relationship (Ve/Vco₂ slope) (33±6 versus 29±4, P<0.001). Chronotropic incompetence was significantly more common in patients with HfpEF compared with matched healthy controls as measured by the percentage of the HR reserve used during maximal exercise (63% versus 2%, <0.001) and percentage of predicted maximal HR (34% versus 2%, <0.001). In addition, abnormal HR recovery 1-minute after exercise (defined as the reduction in the HR from peak exercise 1-minute after exercise) was also significantly more common in patients with HfpEF compared with controls (23% versus 2%, P=0.01). Hypertensive controls showed similar chronotropic response to peak exercise and HR recovery after exercise as healthy controls.Conclusions— Patients with HfpEF have impaired chronotropic incompetence during maximal exercise and abnormal HR recovery after exercise.
Comorbidity and Ventricular and Vascular Structure and Function in Heart Failure With Preserved Ejection Fraction: A Community-Based Study
Circulation: Heart Failure Volume 5, Issue 61 November 2012

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Background—Patients with heart failure and preserved ejection fraction (HFpEF) display increased adiposity and multiple comorbidities, factors that in themselves may influence cardiovascular structure and function. This has sparked debate as to whether HFpEF represents a distinct disease or an amalgamation of comorbidities. We hypothesized that fundamental cardiovascular structural and functional alterations are characteristic of HFpEF, even after accounting for body size and comorbidities.Methods and Results—Comorbidity-adjusted cardiovascular structural and functional parameters scaled to independently generated and age-appropriate allometric powers were compared in community-based cohorts of HFpEF patients (n=386) and age/sex-matched healthy n=193 and hypertensive, n=386 controls. Within HFpEF patients, body size and concomitant comorbidity-adjusted cardiovascular structural and functional parameters and survival were compared in those with and without individual comorbidities. Among HFpEF patients, comorbidities (obesity, anemia, diabetes mellitus, and renal dysfunction) were each associated with unique clinical, structural, functional, and prognostic profiles. However, after accounting for age, sex, body size, and comorbidities, greater concentric hypertrophy, atrial enlargement and systolic, diastolic, and vascular dysfunction were consistently observed in HFpEF compared with age/sex-matched normotensive and hypertensive.Conclusions—Comorbidities influence ventricular-vascular properties and outcomes in HFpEF, yet fundamental disease-specific changes in cardiovascular structure and function underlie this disorder. These data support the search for mechanistically targeted therapies in this disease.
Invasive Assessment of Pulmonary Hypertension: Time for a More Fluid Approach?
- Barry A. Borlaug
Circulation: Heart Failure Volume 7, Issue 11 January 2014

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Wireless Pulmonary Artery Pressure Monitoring Guides Management to Reduce Decompensation in Heart Failure With Preserved Ejection Fraction
- Philip B. Adamson,
- William T. Abraham,
- Robert C. Bourge,
- Maria Rosa Costanzo,
- Ayesha Hasan,
- Chethan Yadav,
- John Henderson,
- Pam Cowart and
- Lynne Warner Stevenson
Circulation: Heart Failure Volume 7, Issue 61 November 2014

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Background—No treatment strategies have been demonstrated to be beneficial for the population for patients with heart failure (HF) and preserved ejection fraction (EF).Methods and Results—The CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial was a prospective, single-blinded, randomized controlled clinical trial testing the hypothesis that hemodynamically guided HF management decreases decompensation leading to hospitalization. Of the 550 patients enrolled in the study, 119 had left ventricular EF ≥40% (average, 50.6%), 430 patients had low left ventricular EF (<40%; average, 23.3%), and 1 patient had no documented left ventricular EF. A microelectromechanical system pressure sensor was permanently implanted in all participants during right heart catheterization. After implant, subjects were randomly assigned in single-blind fashion to a treatment group in whom daily uploaded pressures were used in a treatment strategy for HF management or to a control group in whom standard HF management included weight-monitoring, and pressures were uploaded but not available for investigator use. The primary efficacy end point of HF hospitalization rate >6 months for preserved EF patients was 46% lower in the treatment group compared with control (incidence rate ratio, 0.54; 95% confidence interval, 0.38–0.70; P<0.0001). After an average of 17.6 months of blinded follow-up, the hospitalization rate was 50% lower (incidence rate ratio, 0.50; 95% confidence interval, 0.35–0.70; P<0.0001). In response to pulmonary artery pressure information, more changes in diuretic and vasodilator therapies were made in the treatment group.Conclusions—Hemodynamically guided management of patients with HF with preserved EF reduced decompensation leading to hospitalization compared with standard HF management strategies.Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00531661.
Association Between Use of Statins and Mortality in Patients With Heart Failure and Ejection Fraction of ≥50%
- Urban Alehagen,
- Lina Benson,
- Magnus Edner,
- Ulf Dahlström and
- Lars H. Lund
Circulation: Heart Failure Volume 8, Issue 51 September 2015

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Background—The pathophysiology of heart failure with preserved ejection fraction is poorly understood, but may involve a systemic proinflammatory state. Therefore, statins might improve outcomes in patients with heart failure with preserved ejection fraction defined as ≥50%.Methods and Results—Of 46 959 unique patients in the prospective Swedish Heart Failure Registry, 9140 patients had heart failure and ejection fraction ≥50% (age 77±11 years, 54.0% women), and of these, 3427 (37.5%) were treated with statins. Propensity scores for statin treatment were derived from 40 baseline variables. The association between statin use and primary (all-cause mortality) and secondary (separately, cardiovascular mortality, and combined all-cause mortality or cardiovascular hospitalization) end points was assessed with Cox regressions in a population matched 1:1 based on age and propensity score. In the matched population, 1-year survival was 85.1% for statin-treated versus 80.9% for untreated patients (hazard ratio, 0.80; 95% confidence interval, 0.72–0.89; P<0.001). Statins were also associated with reduced cardiovascular death (hazard ratio, 0.86; 95% confidence interval, 0.75–0.98; P=0.026) and composite all-cause mortality or cardiovascular hospitalization (hazard ratio, 0.89; 95% confidence interval, 0.82–0.96; P=0.003).Conclusions—In heart failure with ejection fraction ≥50%, the use of statins was associated with improved outcomes. The mechanisms should be evaluated and the effects tested in a randomized trial.
Prognostic Importance of Changes in Cardiac Structure and Function in Heart Failure With Preserved Ejection Fraction and the Impact of Spironolactone
- Amil M. Shah,
- Brian Claggett,
- Nancy K. Sweitzer,
- Sanjiv J. Shah,
- Anita Deswal,
- Inder S. Anand,
- Jerome L. Fleg,
- Bertram Pitt,
- Marc A. Pfeffer and
- Scott D. Solomon
Circulation: Heart Failure Volume 8, Issue 61 November 2015

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Background—Limited data exist regarding the impact of aldosterone antagonist therapy on cardiac structure and function in heart failure with preserved ejection fraction and on the prognostic relevance of changes in cardiac structure and function in heart failure with preserved ejection fraction.Methods and Results—Cardiac structure and function were assessed by quantitative echocardiography at baseline and at 12- to 18-month follow-up in 239 patients with heart failure with preserved ejection fraction (left ventricular [LV] ejection fraction [LVEF] ≥45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. The impact of spironolactone therapy on measures of cardiac structure and function was assessed in the study population overall, and change in echocardiographic measures was associated with the subsequent occurrence of the primary composite outcome of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest. Spironolactone was not associated with alterations in cardiac structure and function compared with placebo. Decrease in left atrial volume at follow-up was associated with a lower risk of subsequent occurrence of the primary outcome.Conclusions—Twelve to 18 months of spironolactone therapy was not associated with alterations in cardiac structure or function in patients with heart failure with preserved ejection fraction. Reduction in left atrial volume at follow-up was associated with a lower risk of subsequent occurrence of the primary composite outcome.Clinical Trial Registration—URL: http:///www.clinicaltrials.gov. Unique identifier: NCT00094302.
Reductions in N-Terminal Pro-Brain Natriuretic Peptide Levels Are Associated With Lower Mortality and Heart Failure Hospitalization Rates in Patients With Heart Failure With Mid-Range and Preserved Ejection Fraction
- Gianluigi Savarese,
- Camilla Hage,
- Nicola Orsini,
- Ulf Dahlström,
- Pasquale Perrone-Filardi,
- Giuseppe M.C. Rosano and
- Lars H. Lund
Circulation: Heart Failure Volume 9, Issue 111 November 2016

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Background—In heart failure with mid-range ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF), feasible surrogate end points are needed for phase II trials. The aim was to assess whether a reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) is associated with improved mortality/morbidity in an unselected population of HFmrEF and HFpEF patients.Methods and Results—In the Swedish Heart Failure Registry, HFmrEF (EF=40%–49%) and HFpEF (EF≥50%) patients reporting at least 2 consecutive outpatient NT-proBNP assessments were prospectively studied. Associations between reduction in NT-proBNP and overall mortality, HF hospitalization, and their composite were assessed by multivariable Cox regressions, with NT-proBNP changes modeled as binary (decrease/increase) or quantitative predictor by restricted cubic splines. In 650 patients, at a median of 7 months between the 2 measurements of NT-proBNP and over a median follow-up of 1.65 years, 361 patients (55%) showed a reduction and 289 patients (45%) an increase in NT-proBNP. Change in NT-proBNP was associated with risk of outcomes. Fifty-seven patients (16%) who decreased their NT-proBNP versus 78 patients (27%) who increased it died from any cause (adjusted hazard ratio=0.53; 95% confidence interval=0.36–0.77), 61 (17%) versus 86 (30%) were hospitalized for HF (hazard ratio=0.41; 95% confidence interval=0.29–0.60), and 96 (27%) versus 125 (43%) reported the composite outcome (hazard ratio=0.46; 95% confidence interval=0.34–0.62). These findings were replicated in HFmrEF and HFpEF separately.Conclusions—In HFmrEF and HFpEF during routine care, decreases in NT-proBNP were associated with improved mortality and morbidity. Studies to determine whether NT-proBNP changes in response to therapy predict drug efficacy are needed.
Endothelial Senescence Contributes to Heart Failure With Preserved Ejection Fraction in an Aging Mouse Model
Circulation: Heart Failure Volume 10, Issue 61 June 2017

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Background—Because of global aging, the prevalence of heart failure with preserved ejection fraction (HFpEF) continues to rise. Although HFpEF pathophysiology remains incompletely understood, endothelial inflammation is stated to play a central role. Cellular senescence is a process of cellular growth arrest linked with aging and inflammation. We used mice with accelerated aging to investigate the role of cellular senescence in HFpEF development.Methods and Results—Senescence-accelerated mice (SAM, n=18) and control mice with normal senescence (n=15) were fed normal chow or a high-fat, high-salt diet (WD). Vascular and cardiac function was assessed at 8, 16, and 24 weeks of age. At 24 weeks, both SAM on WD (SAM-WD) and SAM on regular diet displayed endothelial dysfunction, as evidenced by impaired acetylcholine-induced relaxation of aortic segments and reduced basal nitric oxide. At week 24, SAM-WD had developed HFpEF, characterized by diastolic dysfunction, left ventricular hypertrophy, left atrial dilatation, and interstitial fibrosis. Also, exercise capacity was reduced and lung weight increased. Cardiovascular inflammation and senescence were assessed by immunohistochemical and immunofluorescence staining of hearts and aortas. SAM-WD showed increased endothelial inflammation (intercellular adhesion molecule 1 expression) and increased endothelial senescence (acetyl-p53/CD31 costaining). The latter correlated with diastolic function and intercellular adhesion molecule 1 expression.Conclusions—SAM develop endothelial dysfunction. Adding a high-salt, high-fat diet accelerates endothelial senescence and instigates endothelial inflammation. This coincides with hemodynamic and structural changes typical of HFpEF. Targeting endothelial senescence could be a new therapeutic avenue in HFpEF.
INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction): Rationale and Design
- Yogesh N.V. Reddy,
- Gregory D. Lewis,
- Sanjiv J. Shah,
- Martin LeWinter,
- Marc Semigran,
- Victor G. Davila-Roman,
- Kevin Anstrom,
- Adrian Hernandez,
- Eugene Braunwald,
- Margaret M. Redfield and
- Barry A. Borlaug
Circulation: Heart Failure Volume 10, Issue 51 May 2017

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Approximately half of patients with heart failure have preserved ejection fraction. There is no proven treatment that improves outcome. The pathophysiology of heart failure with preserved ejection fraction is complex and includes left ventricular systolic and diastolic dysfunction, pulmonary vascular disease, endothelial dysfunction, and peripheral abnormalities. Multiple lines of evidence point to impaired nitric oxide (NO)-cGMP bioavailability as playing a central role in each of these abnormalities. In contrast to traditional organic nitrate therapies, an alternative strategy to restore NO-cGMP signaling is via inorganic nitrite. Inorganic nitrite, previously considered to be an inert byproduct of NO metabolism, functions as an important in vivo reservoir for NO generation, particularly under hypoxic and acidosis conditions. As such, inorganic nitrite becomes most active at times of greater need for NO signaling, as during exercise when left ventricular filling pressures and pulmonary artery pressures increase. Herein, we present the rationale and design for the INDIE-HFpEF trial (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction), which is a multicenter, randomized, double-blind, placebo-controlled cross-over study assessing the effect of inhaled inorganic nitrite on peak exercise capacity, conducted in the National Heart, Lung, and Blood Institute–sponsored Heart Failure Clinical Research Network.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT02742129.
Right Heart Phenotype in Heart Failure With Preserved Ejection Fraction
- Marco Guazzi and
- Robert Naeije
Circulation: Heart Failure Volume 14, Issue 41 April 2021

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The health burden of heart failure with preserved ejection fraction is increasingly recognized. Despite improvements in diagnostic algorithms and established knowledge on the clinical trajectory, effective treatment options for heart failure with preserved ejection fraction remain limited, mainly because of the high mechanistic heterogeneity. Diagnostic scores, big data, and phenomapping categorization are proposed as key steps needed for progress. In the meantime, advancements in imaging techniques combined to high-fidelity pressure signaling analysis have uncovered right ventricular dysfunction as a mediator of heart failure with preserved ejection fraction progression and as major independent determinant of poor outcome. This review summarizes the current understanding of the pathophysiology of right ventricular dysfunction in heart failure with preserved ejection fraction covering the different right heart phenotypes and offering perspectives on new treatments targeting the right ventricle in its function and geometry.
Efficacy and Safety of Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction According to Age: The DELIVER Trial
- Alexander Peikert,
- Felipe A. Martinez,
- Muthiah Vaduganathan,
- Brian L. Claggett,
- Ian J. Kulac,
- Akshay S. Desai,
- Pardeep S. Jhund,
- Rudolf A. de Boer,
- David DeMets,
- Adrian F. Hernandez,
- Silvio E. Inzucchi,
- Mikhail N. Kosiborod,
- Carolyn S.P. Lam,
- Sanjiv J. Shah,
- Tsvetana Katova,
- Béla Merkely,
- Orly Vardeny,
- Ulrica Wilderäng,
- Daniel Lindholm,
- Magnus Petersson,
- Anna Maria Langkilde,
- John J.V. McMurray and
- Scott D. Solomon
Circulation: Heart Failure Volume 15, Issue 101 October 2022

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Background:The prevalence of heart failure with mildly reduced or preserved ejection fraction markedly increases with age, with older individuals disproportionately facing excess risk for mortality and hospitalization.Methods:The DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) randomized patients with New York Heart Association functional class II–IV and left ventricular ejection fraction >40% to either dapagliflozin or placebo for a median follow-up period of 2.3 years. We examined efficacy and safety outcomes by age categories (<55, 55–64, 65–74, and ≥75 years) and across age as a continuous measure.Results:Among 6263 randomized patients (aged 40–99 years, mean age 71.7±9.6 years), 338 (5.4%) were <55 years, 1007 (16.1%) were 55–64 years, 2326 (37.1%) were 65 to 74 years, and 2592 (41.4%) were ≥75 years. Dapagliflozin reduced the risk of the primary composite outcome compared with placebo in all age categories (P_interaction=0.95) and across the age spectrum as a continuous function (P_interaction=0.76). Similar benefits were observed for the components of the primary outcome, with no significant interaction between randomized treatment and age category. Adverse events occurred more frequently with increasing age, but there were no significant differences in predefined safety outcomes between patients randomized to dapagliflozin and placebo across all age categories.Conclusions:In patients with heart failure and mildly reduced or preserved ejection fraction enrolled in DELIVER, dapagliflozin reduced the combined risk of cardiovascular death or worsening heart failure events across the spectrum of age, with a consistent safety profile, including among the traditionally under-treated older segment of patients ≥75 years.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03619213.
Echocardiographic Features Beyond Ejection Fraction and Associated Outcomes in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction
- Anthony E. Peters,
- Robert M. Clare,
- Karen Chiswell,
- G. Michael Felker,
- Anita Kelsey,
- Robert Mentz and
- Adam D. DeVore
Circulation: Heart Failure Volume 16, Issue 51 May 2023

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Background:Heart failure (HF) guidelines recommend assessment of left ventricular ejection fraction (LVEF) to classify patients and guide therapy implementation. However, LVEF alone may be insufficient to adequately characterize patients with HF, especially those with mildly reduced or preserved LVEF. Recommendations on additional testing are lacking, and there are limited data on use of echocardiographic features beyond LVEF in patients with heart failure with mildly reduced or preserved LVEF.Methods:In patients with HF with mildly reduced or preserved LVEF identified in a large US health care system, the association of the following metrics with mortality was evaluated: LV global longitudinal strain (LV GLS>–16), left atrial volume index (>28 mL/m²), left ventricular hypertrophy (LVH), and E/e´>13 and e´<9. A multivariable model for mortality was constructed including age, sex, and key comorbidities followed by stepwise selection of echocardiographic features. Characteristics and outcomes of subgroups with normal versus abnormal LV GLS and LVEF were evaluated.Results:Among 2337 patients with complete echocardiographic data assessed between 2017 and 2020, the following features were associated with all-cause mortality on univariate analysis over 3 years of follow-up: E/e´+e´, LV GLS, left atrial volume index (all P<0.01). In the multivariable model (C-index=0.65), only abnormal LV GLS was independently associated with all-cause mortality (HR, 1.35 [95% CI, 1.11–1.63]; P=0.002). Among patients with LVEF>55%, 498/1255 (40%) demonstrated abnormal LV GLS. Regardless of specific LVEF, patients with abnormal LV GLS demonstrated a higher burden of multiple comorbidities and higher event rates compared with patients with normal LV GLS.Conclusions:In a large, real-world HF with mildly reduced or preserved LVEF population, echocardiographic features, led by LV GLS, were associated with adverse outcomes irrespective of LVEF. A large proportion of patients demonstrate adverse myocardial function by LV GLS despite preserved LVEF and may represent a key cohort of interest for HF medical therapies and future clinical studies.

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