The roles of exercise stress echocardiography for the evaluation of heart failure with preserved ejection fraction in the heart failure pandemic era.

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly 70% of all HF and has become the dominant form of HF. The increased prevalence of HFpEF has contributed to a rise in the number of HF patients, known as the "heart failure pandemic". In addition to the fact that HF is a progressive disease and a delayed diagnosis may worsen clinical outcomes, the emergence of disease-modifying treatments such as sodium-glucose transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists has made appropriate and timely identification of HFpEF even more important. However, diagnosis of HFpEF remains challenging in patients with a lower degree of congestion. In addition to normal EF, this is related to the fact that left ventricular (LV) filling pressures are often normal at rest but become abnormal during exercise. Exercise stress echocardiography can identify such exercise-induced elevations in LV filling pressures and facilitate the diagnosis of HFpEF. Exercise stress echocardiography may also be useful for risk stratification and assessment of exercise tolerance as well as cardiovascular responses to exercise. Recent attention has focused on dedicated dyspnea clinics to identify early HFpEF among patients with unexplained dyspnea and to investigate the causes of dyspnea. This review discusses the role of exercise stress echocardiography in the diagnosis and evaluation of HFpEF.

Cardiac function, haemodynamics, and valve competence with exercise in patients with heart failure with preserved ejection fraction and mild to moderate secondary mitral regurgitation.

AIMS: This study aimed to evaluate the clinical significance of secondary mitral regurgitation (MR) in patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We conducted a prospective study enrolling consecutively evaluated patients with HFpEF undergoing invasive haemodynamic exercise testing with simultaneous echocardiography. Compared to HFpEF without MR (n = 145, 79.7%), those with mild or moderate MR (n = 37, 20.3%) were older, more likely to be women, had more left ventricular (LV) systolic dysfunction, and more likely to have left atrial (LA) myopathy reflected by greater burden of atrial fibrillation, more LA dilatation, and poorer LA function. Pulmonary artery (PA) wedge pressure was higher at rest in HFpEF with MR (17 ± 5 mmHg vs. 20 ± 5 mmHg, p = 0.005), but there was no difference with exercise. At rest, only 2 (1.1%) patients had moderate MR, and none developed severe MR. Pulmonary vascular resistance was higher, and right ventricular (RV)-PA coupling was more impaired in patients with HFpEF and MR at rest and exercise. LV and LA myocardial dysfunction remained more severe in patients with MR during stress compared to those without MR, characterized by greater LA dilatation during all stages of exertion, lower LA emptying fraction and compliance, steeper and rightward-shifted LA pressure-volume relationships, and reduced LV longitudinal contractile function. CONCLUSIONS: Patients with HFpEF and mild or moderate MR have more severe LV systolic dysfunction, LA myopathy, RV-PA uncoupling, and more severe pulmonary vascular disease. Mitral valve incompetence in this setting is a phenotypic marker of more advanced disease but is not a causal factor in development of HFpEF.

Prognostic utility of cardiopulmonary exercise testing with simultaneous exercise echocardiography in heart failure with preserved ejection fraction.

AIMS: Cardiopulmonary exercise testing (CPET) combined with exercise echocardiography (CPETecho) allows simultaneous assessments of cardiac, pulmonary, and ventilation in heart failure (HF) with preserved ejection fraction (HFpEF). This study sought to determine whether simultaneous assessment of CPET variables could provide additive predictive value over exercise stress echocardiography in patients with dyspnoea. METHODS AND RESULTS: CPETecho was performed in 443 patients with suspected HFpEF (240 HFpEF and 203 controls without HF). Patients with HFpEF were divided based on peak oxygen consumption (VO2, ≥10 or <10 ml/min/kg) or the slope of minute ventilation to carbon dioxide production (VE vs. VCO2 slope ≥45.0 or <45.0). The primary endpoint was defined as a composite of all-cause mortality, HF hospitalization, unplanned hospital visits requiring intravenous diuretics, or intensification of oral diuretics. During a median follow-up of 399 days, the composite outcome occurred in 57 patients. E/e' ratio during peak exercise was associated with adverse outcomes. Patients with HFpEF and lower peak VO2 had increased risks of the composite event (hazard ratio [HR] 5.05, 95% confidence interval [CI] 2.65-9.62, p < 0.0001 vs. controls; HR 3.14, 95% CI 1.69-5.84, p = 0.0003 vs. HFpEF with higher peak VO2). Elevated VE versus VCO2 slope was also associated with adverse events in HFpEF. The addition of either the presence of abnormal peak VO2 or VE versus VCO2 slope increased the predictive ability over the model based on age, sex, atrial fibrillation, left atrial volume index, and exercise E/e' (p < 0.05). CONCLUSION: These data provide new insights into the role of CPETecho in patients with HFpEF.

Imaging and Mechanisms of Heart Failure with Preserved Ejection Fraction: A State of the Art Review.

Understanding of the pathophysiology of heart failure with preserved ejection fraction (HFpEF) has advanced rapidly over the past two decades. Currently, HFpEF is recognized as a heterogeneous syndrome, and there is a growing movement towards developing personalized treatments based on phenotype-guided strategies. Left ventricular dysfunction is a fundamental pathophysiological abnormality in HFpEF; however, recent evidence also highlights significant roles for the atria, right ventricle, pericardium, and extracardiac contributors. Imaging plays a central role in characterizing these complex and highly integrated domains of pathophysiology. This review focuses on established evidence, recent insights, and the challenges that need to be addressed concerning the pathophysiology of HFpEF, with a focus on imaging-based evaluations and opportunities for further research.

Exercise Stress Echocardiography-Based Phenotyping of Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome requiring improved phenotypic classification. Previous studies have identified subphenotypes of HFpEF, but the lack of exercise assessment is a major limitation. The aim of this study was to identify distinct pathophysiologic clusters of HFpEF based on clinical characteristics, and resting and exercise assessments. METHODS: A total of 265 patients with HFpEF underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. Cluster analysis was performed by the K-prototype method with 21 variables (10 clinical and resting echocardiographic variables and 11 exercise echocardiographic parameters). Pathophysiologic features, exercise tolerance, and prognosis were compared among phenogroups. RESULTS: Three distinct phenogroups were identified. Phenogroup 1 (n = 112 [42%]) was characterized by preserved biventricular systolic reserve and cardiac output augmentation. Phenogroup 2 (n = 58 [22%]) was characterized by a high prevalence of atrial fibrillation, increased pulmonary arterial and right atrial pressures, depressed right ventricular systolic functional reserve, and impaired right ventricular-pulmonary artery coupling during exercise. Phenogroup 3 (n = 95 [36%]) was characterized by the smallest body mass index, ventricular and vascular stiffening, impaired left ventricular diastolic reserve, and worse exercise capacity. Phenogroups 2 and 3 had higher rates of composite outcomes of all-cause mortality or heart failure events than phenogroup 1 (log-rank P = .02). CONCLUSION: Exercise echocardiography-based cluster analysis identified three distinct phenogroups of HFpEF, with unique exercise pathophysiologic features, exercise capacity, and clinical outcomes.

Autoimmune Disorders in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Inflammation plays a fundamental role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). In most patients, inflammation develops secondary to cardiometabolic comorbidities, but in some, HFpEF develops in the setting of an underlying systemic inflammatory disease such as rheumatoid arthritis or systemic lupus erythematosus. OBJECTIVES: This study aimed to investigate the prevalence, pathophysiology, and outcome of patients with HFpEF and autoimmune or primary inflammatory disorders. METHODS: Of 982 consecutively evaluated patients with HFpEF diagnosed, 79 (8.0%) had autoimmune disorders. HFpEF was defined by invasive cardiopulmonary hemodynamic exercise testing. RESULTS: Female sex, higher heart rate, lower hemoglobin, absence of atrial fibrillation, and absence of coronary artery disease were independently associated with autoimmune disorders. Hemodynamics at rest and exercise did not differ between the groups, but peripheral oxygen extraction was lower in those with autoimmune disorders, reflected by lower arterial-venous oxygen content difference at rest (4.2 ± 0.7 mL/dL vs 4.6 ± 1.0 mL/dL; P < 0.001) and during exercise (9.3 ± 2.2 mL/dL vs 10.4 ± 2.2 mL/dL; P < 0.001), suggesting a greater peripheral deficit, and ventilatory efficiency (VE/VCo2 slope, regression slope relating minute ventilation to carbon dioxide output) was also more impaired (38.0 ± 7.9 vs 36.2 ± 7.3; P = 0.043). Patients with autoimmune disorders had a higher risk of death or heart failure (HF) hospitalization compared with those without in adjusted analyses (HR: 1.95 [95% CI: 1.17-3.27]; P = 0.011) over a median follow-up of 3.0 years, which was primarily attributable to higher risk of HF hospitalization (HR: 2.87 [95% CI: 1.09-7.57]; P = 0.033). CONCLUSIONS: Patients with HFpEF and autoimmune disorders have similar hemodynamic derangements but greater peripheral deficits in oxygen transport and higher risk for adverse outcome compared with those without.

The Natural History of Atrial Functional Mitral Regurgitation.

BACKGROUND: The natural history of moderate/severe atrial functional mitral regurgitation (AFMR) is unknown. OBJECTIVES: The authors sought to study the incidence of left ventricular (LV) systolic dysfunction (LVSD), progression or regression of ≥mild-moderate AFMR, and impact on mortality. METHODS: Adults with left atrial (LA) volume index ≥40 mL/m2, ≥mild-moderate AFMR, and follow-up echocardiogram were followed for incident LVSD (ejection fraction <50% and ≥10% lower than baseline), progression of mild-moderate/moderate AFMR to severe, and persistent regression of AFMR to no/trivial. Relation of AFMR progression or regression as time-dependent covariates with all-cause mortality was studied. Incidence of LVSD was compared with patients with no/mild AFMR matched on age, sex, comorbidities and ejection fraction. Patients were followed until mitral intervention, myocardial infarction, or last follow-up. RESULTS: A total of 635 patients (median age 75 years, 51% female, 96% mild-moderate/moderate AFMR, 4% severe AFMR) were included. Over a median 2.2 years (Q1-Q3: 1.0-4.3 years), incidence rates per 100 person-years were 3.2 for LVSD (P = 0.52 vs patients with no/mild AFMR), 1.9 for progression of AFMR, and 3.9 for regression. Female sex and larger LA volume index were independently associated with progression, whereas younger age, male sex, absent atrial fibrillation, and higher LA emptying fraction were independently associated with regression. Neither AFMR progression nor regression was independently associated with mortality. Instead, independent risk factors for mortality included older age, concentric LV geometry, and higher estimated LV filling and pulmonary pressures. CONCLUSIONS: In patients with predominantly mild-moderate/moderate AFMR, regression of MR was more common than progression, but neither was associated with mortality. Instead, diastolic function abnormalities were more important. Over a median 2-year follow-up, LVSD risk was not increased.

Prevalence and risk factors for medication-refractory reflux esophagitis in patients with systemic sclerosis in Japan.

BACKGROUNDS: Patients with systemic sclerosis (SSc) often have esophageal motility abnormalities and weak esophago-gastric junction (EGJ) barrier function, which causes proton pump inhibitor (PPI)-refractory reflux esophagitis (RE). The aims of this study were to clarify the current management of RE and prevalence and risk factors of medication-refractory RE in patients with SSc in Japan. METHODS: A total of 188 consecutive patients with SSc who underwent both esophageal high-resolution manometry (HRM) and esophagogastroduodenoscopy (EGD) were reviewed. The presence of RE and grades of the gastroesophageal flap valve (GEFV) were assessed. Esophageal motility was assessed retrospectively according to the Chicago classification v3.0. When RE was seen on a standard dose of PPI or any dose of vonoprazan (VPZ), it was defined as medication-refractory RE. RESULTS: Approximately 80% of patients received maintenance therapy with acid secretion inhibitors regardless of esophageal motility abnormalities. Approximately 50% of patients received maintenance therapy with PPI, and approximately 30% of patients received VPZ. Medication-refractory RE was observed in 30 patients (16.0%). In multivariable analyses, the number of EGD and absent contractility were significant risk factors for medication-refractory RE. Furthermore, combined absent contractility and GEFV grade III or IV had higher odds ratios than did absent contractility alone. CONCLUSIONS: Patients with persistent reflux symptoms and those with absent contractility and GEFV grade III or IV should receive maintenance therapy with strong acid inhibition to prevent medication-refractory RE.

Pathophysiologic and prognostic importance of cardiac power output reserve in heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by multiple cardiac reserve limitations during exercise. Cardiac power output (CPO) is an index of global cardiac performance and can be estimated non-invasively by echocardiography. We hypothesized that CPO reserve during exercise would be associated with impaired cardiovascular reserve, exercise intolerance, and adverse outcomes in HFpEF. METHODS AND RESULTS: Exercise stress echocardiography was performed in 425 dyspnoeic patients [217 HFpEF and 208 non-heart failure (HF) controls] to estimate CPO at rest and during exercise. We classified patients with HFpEF based on the median value of changes in CPO from rest to peak exercise (ΔCPO >0.49 W/100 g). Patients with HFpEF and a lower CPO reserve had poorer biventricular systolic function, impaired chronotropic response during exercise, and worse aerobic capacity than controls and those with a higher CPO reserve. During a median follow-up of 358 days, a composite outcome of all-cause mortality or HF events occurred in 30 patients. Patients with a lower CPO reserve had four-fold and nearly 10-fold increased risks of the outcomes compared with those with a higher CPO reserve and controls, respectively [hazard ratio (HR) 4.05, 95% confidence interval (CI) 1.16-10.1, P = 0.003 and HR 9.61, 95% CI 3.58-25.8, P < 0.0001]. We further found that a lower CPO reserve had an incremental prognostic value over the H2FPEF score and exercise duration. In contrast, resting CPO did not predict clinical outcomes in patients with HFpEF. CONCLUSION: A lower CPO reserve was associated with biventricular systolic dysfunction, chronotropic incompetence, exercise intolerance, and adverse outcomes in patients with HFpEF.

Characterization and prognostic importance of chronotropic incompetence in heart failure with preserved ejection fraction.

BACKGROUND: Exercise intolerance is the primary symptom of patients with heart failure with preserved ejection fraction (HFpEF). Chronotropic incompetence has been considered to be common and contribute to poor exercise capacity in HFpEF. However, clinical characteristics, pathophysiology, and outcomes of chronotropic incompetence in HFpEF remain poorly understood. METHODS: Patients with HFpEF (n = 246) underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. The patients were divided into two groups based on the presence of chronotropic incompetence, which was defined by heart rate reserve <0.80. RESULTS: Chronotropic incompetence was common in HFpEF (n = 112, 41 %). Compared to HFpEF patients with a normal chronotropic response (n = 134), those with chronotropic incompetence had higher body mass index, a higher prevalence of diabetes, more frequent ß-blocker use, and worse New York Heart Association class. During peak exercise, patients with chronotropic incompetence demonstrated less increase in cardiac output and arterial oxygen delivery (cardiac output × saturation × hemoglobin × 1.34 × 10), higher metabolic work (peak oxygen consumption [VO2]/watt), an inability to increase arteriovenous oxygen difference, and poorer exercise capacity (lower peak VO2) than those without. Chronotropic incompetence was associated with higher rates of a composite of all-cause mortality or worsening HF events (hazard ratio, 2.66, 95 % confidence intervals, 1.16-6.09, p = 0.02). CONCLUSION: Chronotropic incompetence is common in HFpEF, and is associated with unique pathophysiologic characteristics during exercise and clinical outcomes.

Contributions of anemia to exercise intolerance in heart failure with preserved ejection fraction-An exercise stress echocardiographic study.

Aims: Anemia is common in patients with heart failure with preserved ejection fraction (HFpEF) and is associated with exercise intolerance. However, there are limited data on how anemia contributes to reduced exercise capacity in patients with HFpEF. We aimed to characterize exercise capacity, cardiovascular and ventilatory reserve, and the oxygen (O2) pathway in anemic patients with HFpEF. Methods: A total of 238 patients with HFpEF and 248 dyspneic patients without HF underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. Patients with HFpEF were classified into two groups based on the presence of anemia (hemoglobin < 13.0 g/dL in men and < 12.0 g/dL in women). Results: Anemic HFpEF patients (n = 112) had worse nutritional status and renal function, lower iron levels, and greater left ventricular (LV) remodeling and plasma volume expansion than those without anemia (n = 126). Exercise capacity, assessed by peak oxygen consumption, exercise intensity, and exercise duration, was lower in the anemic HFpEF group than in the other groups. Despite a similar cardiac output during exercise, anemic patients with HFpEF demonstrated limitations in arterial O2 delivery, lower arteriovenous O2 content difference, and ventilatory inefficiency (higher minute ventilation vs. carbon dioxide production slope) during peak exercise. Conclusion: Anemic HFpEF patients demonstrated unique pathophysiological features with greater LV remodeling and plasma volume expansion, limitations in arterial O2 delivery and peripheral O2 extraction, and ventilatory inefficiency, which may contribute to reduced exercise capacity. Further studies are needed to develop an optimal approach for treating anemia in patients with HFpEF.

Effects of Mineralocorticoid Receptor Antagonists in Early-Stage Heart Failure With Preserved Ejection Fraction.

Background: Hospitalization with a first episode of heart failure (HF) is a serious event associated with poor clinical outcomes in HF with preserved ejection fraction (HFpEF). Identification of HFpEF via detection of elevated left ventricular filling pressure at rest or during exercise may allow early intervention. Benefits of treatment with mineralocorticoid receptor antagonists (MRAs) in established HFpEF have been reported, but use of MRAs is not well studied in early HFpEF without prior HF hospitalization. Methods: We retrospectively studied 197 patients with HFpEF who did not have prior hospitalization but had been diagnosed by exercise stress echocardiography or catheterization. We examined changes in natriuretic peptide levels and echocardiographic parameters reflecting diastolic function following MRA initiation. Results: Of the 197 patients with HFpEF, MRA treatment was initiated for 47 patients. After a median 3-month follow-up, reduction in N-terminal pro-B-type natriuretic peptide levels from baseline to follow-up was greater in patients treated with MRA than in those who were not (median, -200 pg/mL [interquartile range, -544 to -31] vs 67 pg/mL [interquartile range, -95 to 456], P < 0.0001 in 50 patients with paired data). Similar results were observed for the changes in B-type natriuretic peptide levels. Reduction in the left atrial volume index was also greater in the MRA-treated group than in the non-MRA-treated group after a median 7-month follow-up (77 patients with paired echocardiographic data). Patients with lower left ventricular global longitudinal strain experienced a greater reduction in N-terminal pro-B-type natriuretic peptide levels following MRA treatment. In the safety assessment, MRA modestly decreased renal function but did not change potassium levels. Conclusions: Our results suggest that MRA treatment has potential benefits for early-stage HFpEF.

Contexte: L'hospitalisation consécutive à un premier épisode d'insuffisance cardiaque (IC) est un événement grave associé à des résultats cliniques médiocres dans l'IC à fraction d'éjection préservée (ICFEP). Or, la détection d'une pression de remplissage ventriculaire gauche élevée au repos ou à l'effort peut permettre de déceler une ICFEP et d'intervenir de façon précoce. Par ailleurs, le recours à des antagonistes des récepteurs minéralocorticoïdes (ARM) serait bénéfique dans les cas d'ICFEP, mais leur utilisation n'a pas été bien étudiée dans l'ICFEP précoce sans hospitalisation préalable pour cause d'insuffisance cardiaque. Méthodologie: Nous avons étudié rétrospectivement 197 patients atteints d'ICFEP qui n'avaient pas été hospitalisés auparavant, mais dont la maladie avait été diagnostiquée par une échocardiographie de stress ou un cathétérisme. Après l'instauration des ARM, nous avons examiné les variations des taux de peptides natriurétiques et des paramètres échocardiographiques reflétant la fonction diastolique. Résultats: Sur les 197 patients atteints d'ICFEP, 47 ont entamé un traitement par des ARM. Après un suivi médian de trois mois, la réduction des taux de propeptides natriurétiques de type B N-terminal (NT-proBNP) entre la valeur initiale et le suivi était plus importante chez les patients traités par des ARM que chez ceux qui ne l'étaient pas (médiane : -200 pg/ml [écart interquartile : -544 à -31] contre 67 pg/ml [écart interquartile : -95 à 456], p < 0,0001 chez 50 patients ayant des données appariées). Des résultats similaires ont été observés pour la variation des taux de peptides natriurétiques de type B. La réduction du volume de l'oreillette gauche était également plus importante dans le groupe traité par des ARM que dans le groupe témoin après un suivi médian de sept mois (données échocardiographiques appariées pour 77 patients). Les patients présentant une déformation longitudinale globale du ventricule gauche plus faible ont connu une réduction plus importante des taux de NT-proBNP après le traitement par des ARM. Enfin, lors de l'évaluation de l'innocuité, les ARM ont légèrement altéré la fonction rénale, mais sans modifier les taux de potassium. Conclusions: Ces résultats semblent indiquer que le traitement par des ARM présente des avantages potentiels dans les cas d'ICFEP au stade précoce.

Pathophysiologic Contributions of Visceral Adiposity to Left Ventricular Diastolic Dysfunction.

BACKGROUND: Visceral fat produces inflammatory cytokines and may play a major role in heart failure with preserved ejection fraction (HFpEF). However, little data exist regarding how qualitative and quantitative abnormalities of visceral fat would contribute to left ventricular diastolic dysfunction (LVDD). METHODS: We studied 77 participants who underwent open abdominal surgery for intra-abdominal tumors (LVDD, n = 44; controls without LVDD, n = 33). Visceral fat samples were obtained during the surgery, and mRNA levels of inflammatory cytokines were measured. Visceral and subcutaneous fat areas were measured using abdominal computed tomography. RESULTS: Patients with significant LVDD had greater LV remodeling and worse LVDD than controls. While body weight, body mass index, and subcutaneous fat area were similar in patients with LVDD and controls, the visceral fat area was larger in patients with LVDD than in controls. The visceral fat area was correlated with BNP levels, LV mass index, mitral e' velocity, and E/e' ratio. There were no significant differences in the mRNA expressions of visceral adipose tissue cytokines (IL-2, -6, -8, and -1ß, TNFα, CRP, TGFß, IFNγ, leptin, and adiponectin) between the groups. CONCLUSIONS: Our data may suggest the pathophysiological contribution of visceral adiposity to LVDD.

Epidemiology, Pathophysiology, Diagnosis, and Therapy of Heart Failure With Preserved Ejection Fraction in Japan.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a global health care problem, with diagnostic difficulty, limited treatment options and high morbidity and mortality rates. The prevalence of HFpEF is increasing because of the aging population and the increasing burden of cardiac and metabolic comorbidities, such as systemic hypertension, diabetes, chronic kidney disease, and obesity. The knowledge base is derived primarily from the United States and Europe, and data from Asian countries, including Japan, remain limited. Given that phenotypic differences may exist between Japanese and Western patients with HFpEF, careful characterization may hold promise to deliver new therapy specific to the Japanese population. In this review, we summarize the current knowledge regarding the epidemiology, pathophysiology and diagnosis of and the potential therapies for HFpEF in Japan.

Diagnostic value of reduced left atrial compliance during ergometry exercise in heart failure with preserved ejection fraction.

AIMS: Diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging in patients presenting with chronic dyspnoea. We sought to determine the diagnostic value of reduced left atrial (LA) compliance during exercise to diagnose HFpEF. METHODS AND RESULTS: Ergometry exercise stress echocardiography was performed in 225 patients with HFpEF and 262 non-heart failure controls (non-cardiac dyspnoea [NCD]) in Protocol 1, where the diagnosis of HFpEF was defined by the HFA-PEFF algorithm. In Protocol 2, the diagnosis of HFpEF was ascertained by exercise right heart catheterization in 67 participants (49 HFpEF and 18 NCD). Speckle-tracking echocardiography was performed at rest and during exercise to determine LA compliance (ratio of LA reservoir strain to E/e'). As compared with NCD, patients with HFpEF demonstrated decreased LA reservoir strain and compliance at rest, and these differences further increased during exercise in Protocol 1. Exercise LA compliance discriminated HFpEF from NCD (area under the curve 0.87, p < 0.0001), with a superior diagnostic ability to exercise E/e' ratio (DeLong p = 0.005). Exercise LA compliance demonstrated incremental diagnostic value over clinical factors (age, systemic hypertension, and atrial fibrillation) and resting LA compliance (χ2 212.4 vs. 166.2, p < 0.0001). These findings were confirmed in Protocol 2. CONCLUSION: Left atrial compliance during exercise demonstrated superior diagnostic ability to exercise E/e' ratio, with incremental diagnostic value over the resting LA compliance. Exercise LA compliance may enhance the diagnosis of HFpEF among patients with dyspnoea.

Prognostic benefit of early diagnosis with exercise stress testing in heart failure with preserved ejection fraction.

BACKGROUND: Delayed diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF) can lead to poor clinical outcomes. Exercise stress testing, especially exercise stress echocardiography, plays a primary role in the early detection of HFpEF among dyspnoeic patients, but its prognostic significance is unknown, as is whether initiation of guideline-directed therapy could improve clinical outcomes in such early-stage HFpEF. METHODS AND RESULTS: Ergometry exercise stress echocardiography was performed in 368 patients with exertional dyspnoea. Heart failure with preserved ejection fraction was diagnosed by a total score of HFA-PEFF algorithm Step 2 (resting assessments) and Step 3 (exercise testing) ≥ 5 or elevated pulmonary capillary wedge pressure at rest or during exercise. The primary endpoint comprised all-cause mortality and worsening HF events. Heart failure with preserved ejection fraction was diagnosed in 182 patients, while 186 had non-cardiac dyspnoea (controls). Patients diagnosed with HFpEF had a seven-fold increased risk of composite events than that of controls [hazard ratio (HR) 7.52; 95% confidential interval (CI), 2.24-25.2; P = 0.001]. Patients with an HFA-PEFF Step 2 < 5 points but had an HFA-PEFF ≥ 5 after exercise stress testing (Steps 2-3) had a higher risk of composite events than controls. Guideline-recommended therapies were initiated in 90 patients diagnosed with HFpEF after index exercise testing. Patients with early treatment experienced lower rates of composite outcomes than those without (HR 0.33; 95% CI, 0.12-0.91; P = 0.03). CONCLUSION: Identification of HFpEF by exercise stress testing may allow risk stratification in dyspnoeic patients. Furthermore, initiation of guideline-directed therapy may be associated with improved clinical outcomes in patients with early-stage HFpEF. LAY SUMMARY: Delayed diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF) can lead to poor clinical outcomes. Exercise stress testing, especially exercise stress echocardiography, plays a primary role in the early identification of HFpEF among dyspnoeic patients, but its prognostic significance is unknown, as is whether initiation of guideline-directed therapy could improve clinical outcomes in such early-stage HFpEF. In the current study, ergometry exercise stress echocardiography was performed in 368 patients with exertional dyspnoea. Heart failure with preserved ejection fraction was diagnosed by the established algorithm consisting of Step 2 (resting assessments) and Step 3 (exercise echocardiography or exercise right heart catheterization). The primary endpoint comprised all-cause mortality and worsening HF events. Heart failure with preserved ejection fraction was diagnosed in 182 patients and non-cardiac dyspnoea (controls) in 186 patients. Patients newly diagnosed with HFpEF had a seven-fold increased risk of composite events than that of controls. Guideline-recommended therapies were initiated in 90 patients newly diagnosed with HFpEF after index exercise testing. Patients with early treatment experienced lower rates of composite outcomes than those without. In conclusion, identification of HFpEF by exercise stress testing may allow risk stratification in patients with chronic exertional dyspnoea. Furthermore, initiation of guideline-directed therapy may be associated with improved clinical outcomes in patients with early-stage HFpEF.

Diagnostic value of expired gas analysis in heart failure with preserved ejection fraction.

Cardiopulmonary exercise testing (CPET) may potentially differentiate heart failure (HF) with preserved ejection fraction (HFpEF) from noncardiac causes of dyspnea (NCD). While contemporary guidelines for HF recommend using CPET for identifying causes of unexplained dyspnea, data supporting this practice are limited. This study aimed to determine the diagnostic value of expired gas analysis to distinguish HFpEF from NCD. Exercise stress echocardiography with simultaneous expired gas analysis was performed in patients with HFpEF (n = 116) and those with NCD (n = 112). Participants without dyspnea symptoms were also enrolled as controls (n = 26). Exercise capacity was impaired in patients with HFpEF than in controls and those with NCD, evidenced by lower oxygen consumption (VO2), but there was a substantial overlap between HFpEF and NCD. Receiver operating characteristic curve analyses showed modest diagnostic abilities of expired gas analysis data in differentiating individuals with HFpEF from the controls; however, none of these variables clearly differentiated between HFpEF and NCD (all areas under the curve < 0.61). Expired gas analysis provided objective assessments of exercise capacity; however, its diagnostic value in identifying HFpEF among patients with symptoms of exertional dyspnea was modest.

Disproportionate exercise-induced pulmonary hypertension in relation to cardiac output in heart failure with preserved ejection fraction: a non-invasive echocardiographic study.

AIMS: Pulmonary hypertension (PH) and pulmonary vascular remodelling are common in patients with heart failure with preserved ejection fraction (HFpEF). Many patients with HFpEF demonstrate an abnormal pulmonary haemodynamic response to exercise that is not identifiable at rest. This can be estimated non-invasively by the mean pulmonary artery pressure-cardiac output relationship (mPAP/CO slope). We sought to characterize the pathophysiology of disproportionate exercise-induced PH in relation to CO (DEi-PH) and its prognostic impact in patients with HFpEF. METHODS AND RESULTS: A total of 345 patients (166 HFpEF and 179 controls) underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. DEi-PH was defined as the mPAP/CO slope >5.2 mmHg/L/min (median value). At rest, there were no differences in right ventricular (RV) function and severity of PH between HFpEF patients with and without DEi-PH. Compared with controls (n = 179) and HFpEF without DEi-PH (n = 83), HFpEF with DEi-PH (n = 83) demonstrated worse exercise capacity (lower peak oxygen consumption), depressed RV systolic function, impaired RV-pulmonary artery coupling, limitation in CO augmentation, more right-sided congestion, and worse ventilatory efficiency (higher minute ventilation vs. carbon dioxide volume) during peak exercise. Kaplan-Meier analyses showed that HFpEF patients with DEi-PH had higher rates of composite outcomes of all-cause mortality or heart failure events than those without (log-rank p = 0.0002). CONCLUSION: Patients with HFpEF and DEi-PH demonstrated distinct pathophysiologic features that become apparent only during exercise. These data suggest that DEi-PH is a pathophysiologic phenotype of HFpEF and reinforce the importance of exercise stress echocardiography for detailed characterization of HFpEF.

Incremental diagnostic value of post-exercise lung congestion in heart failure with preserved ejection fraction.

AIMS: Lung ultrasound (LUS) may unmask occult heart failure with preserved ejection fraction (HFpEF) by demonstrating an increase in extravascular lung water (EVLW) during exercise. Here, we sought to examine the dynamic changes in ultrasound B-lines during exercise to identify the optimal timeframe for HFpEF diagnosis. METHODS AND RESULTS: Patients with HFpEF (n = 134) and those without HF (controls, n = 121) underwent a combination of exercise stress echocardiography and LUS with simultaneous expired gas analysis to identify exercise EVLW. Exercise EVLW was defined by B-lines that were newly developed or increased during exercise. The E/e' ratio peaked during maximal exercise and immediately decreased during the recovery period in patients with HFpEF. Exercise EVLW was most prominent during the recovery period in patients with HFpEF, while its prevalence did not increase from peak exercise to the recovery period in controls. Exercise EVLW was associated with a higher E/e' ratio and pulmonary artery pressure, lower right ventricular systolic function, and elevated minute ventilation to carbon dioxide production (VE vs. VCO2) slope during peak exercise. Increases in B-lines from rest to the recovery period provided an incremental diagnostic value to identify HFpEF over the H2FPEF score and resting left atrial reservoir strain. CONCLUSION: Exercise EVLW was most prominent early during the recovery period; this may be the optimal timeframe for imaging ultrasound B-lines. Exercise stress echocardiography with assessments of recovery EVLW may enhance the diagnosis of HFpEF.