Sorimachi, Hidemi

Abstract Background and Aims Exercise stress echocardiography is recommended as an alternative to invasive testing for diagnosing heart failure with preserved ejection fraction (HFpEF), but an evidence-based operational framework guiding its application is lacking. Methods Patients with chronic unexplained dyspnoea underwent invasive haemodynamic exercise testing with simultaneous echocardiography to test the hypotheses that (i) the current diagnostic algorithms (H2FPEF, HFA-PEFF, and HFpEF-ABA scores) could be enhanced when combined with exercise echocardiography; and (ii) incorporating resting left atrial (LA) compliance (LA reservoir strain divided by E/e′) could further improve diagnostic triage, using separate cut points optimizing sensitivity and specificity. Findings were then validated in an international multicentre cohort. Results Of 482 patients, HFpEF was present in 386 and non-cardiac dyspnoea in 96. Sensitivity to detect HFpEF was only 55%–60% and accuracy 61%–67% using individual diagnostic scores with currently recommended exercise echocardiography. Addition of abnormal resting LA compliance to exercise echocardiography increased sensitivity to 84%–85% but increased the false-positive rate to 31%–43%. Applying separate cut points that optimize specificity and sensitivity (either exercise E/e′ ≥ 13.8 or resting LA compliance ≤1.6% to rule-in HFpEF; both exercise E/e′ < 7.2 and resting LA compliance >4.4% to rule-out HFpEF, remaining patients indeterminate who require invasive testing) improved sensitivity to 95%–99% among definitively classified patients and reduced the number of patients that require invasive exercise testing from ∼60% to ∼30%. Findings were replicated in a multicentre, international validation cohort of patients undergoing rest–exercise echocardiography and invasive exercise testing. Conclusions Currently used non-invasive approaches to HFpEF diagnosis have inadequate sensitivity, indicating that exercise echocardiography cannot supplant invasive testing. Addition of LA strain imaging with optimized rule-in or rule-out values improves diagnostic triage by expanding non-invasive rule-in/rule-out classifications while identifying patients who still require invasive testing in the evaluation of HFpEF.

Abstract Aims The pathophysiology of tricuspid regurgitation (TR) during exercise in heart failure with preserved ejection fraction (HFpEF) is not well understood. Methods and results We investigated dynamic changes in TR severity during exercise in patients with HFpEF and associated relationships with haemodynamics, cardiopulmonary reserve, and prognosis using invasive haemodynamic exercise testing with simultaneous echocardiography and expired gas analysis. Among 169 patients with HFpEF (91 no TR, 44 mild TR, 34 ≥ moderate TR), older age and atrial fibrillation were more common in patients with greater TR severity. Right heart remodelling and dysfunction were more frequently observed with greater TR severity, particularly in the right atrium, along with stepwise increases in right atrial (RA) pressure and interventricular septal flattening, and decreases in cardiac output (CO). During exercise, TR severity frequently worsened, and over half of the patients with moderate TR at rest displayed severe TR during exercise, accompanied by profound RA dilatation, reduced RA reservoir strain, increased septal flattening, and more severely impaired CO reserve. Abnormalities in tricuspid annular motion and ventricular interaction were amplified by exercise with greater TR, but exercise pulmonary vascular pressures did not differ across groups. Patients with ≥ moderate TR during exercise displayed higher event rates (hazard ratio 2.85, 95% confidence interval 1.18–6.85), but patients with mild TR had similar prognosis as those without TR in adjusted models. Conclusions Tricuspid regurgitation in HFpEF is related to advanced RA myopathy and often worsens during exercise leading to dynamic right-sided heart failure, exaggerated ventricular interaction, impaired CO reserve, and increased risk for adverse outcomes. These data emphasize the clinical importance of exercise evaluation and call for further study of novel treatments in those with significant resting and provocable TR.

Abstract Aims The diagnostic difficulty of heart failure with preserved ejection fraction (HFpEF) is related to the fact that many patients develop abnormal hemodynamics only during exercise. Exercise stress echocardiography is a first-line test to unmask such abnormalities, but exercise protocols and diagnostic criteria have not been established. It remains unclear how cardiologists diagnose HFpEF by exercise echocardiography in real-world practice. Methods and Results An international web-based survey was performed on 87 cardiologists, 59% of whom had ≥ 6 years of experience with exercise echocardiography. A retrospective cohort of 652 dyspneic patients who underwent exercise echocardiography was used to determine the impact of different diagnostic criteria on the proportion of HFpEF diagnosis. The most commonly used exercise echocardiography criterion for the HFpEF diagnosis was the HFA-PEFF algorithm (48%), followed by the ASE/EACVI criteria (24%) and some combinations of multiple parameters (22%). A retrospective study found that the proportion of HFpEF diagnosis varied substantially between the criteria used: 20.1% for the ASE/EACVI criteria and 44.3% for the HFA-PEFF algorithm. A survey demonstrated that 54% of the participating cardiologists would initiate sodium-glucose co-transporter 2 inhibitors based on exercise echocardiography results. Conclusion In real-world practice, exercise echocardiography criteria for HFpEF diagnosis vary among cardiologists. While many cardiologists consider initiating pharmacological treatment on exercise echocardiography results, the frequency of HFpEF diagnosis varies substantially depending on the diagnostic criteria used. The lack of universal diagnostic criteria may limit the delivery of evidence-based treatment to patients with HFpEF.

ImportanceIncreases in pulmonary capillary wedge pressure (PCWP) during exercise reduce pulmonary artery (PA) compliance, increase pulsatile right ventricular (RV) afterload, and impair RV-PA coupling in patients with heart failure with preserved ejection fraction (HFpEF). The effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on pulmonary vascular properties and RV-PA coupling are unknown.ObjectiveTo test the effect of dapagliflozin on right ventricular performance and pulmonary vascular load during exertion in HFpEF.Design, Setting, and ParticipantsEvaluation of the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction (CAMEO-DAPA) randomized clinical trial demonstrated improvement in PCWP at rest and exercise over 24 weeks with dapagliflozin compared with placebo with participants recruited between February 2021 and May 2022. This secondary analysis evaluates the effects of dapagliflozin on pulsatile pulmonary vascular load and RV-PA coupling using simultaneous echocardiography and high-fidelity invasive hemodynamic testing with exercise. This was a single-center study including patients with hemodynamically confirmed HFpEF with exercise PCWP of 25 mm Hg or greater.InterventionsDapagliflozin or placebo for 24 weeks.Main Outcomes and MeasuresPulsatile pulmonary vascular load (PA compliance and elastance) and right ventricular performance (PA pulsatility index, RV systolic velocity [s′]/PA mean) during rest and exercise.ResultsAmong 37 randomized participants (mean [SD] age, 67.4 [8.5] years; 25 female [65%]; mean [SD] body mass index, 34.9 [6.7]; calculated as weight in kilograms divided by height in meters squared), there was no effect of dapagliflozin on PA loading or RV-PA interaction at rest. However, with exercise, dapagliflozin improved PA compliance (placebo-corrected mean difference, 0.57 mL/mm Hg; 95% CI, 0.11-1.03 mL/mm Hg; P = .02) and decreased PA elastance (stiffness; −0.17 mm Hg/mL; 95% CI, −0.28 to −0.07 mm Hg/mL; P = .001). RV function during exercise improved, with increase in PA pulsatility index (0.33; 95% CI, 0.08-0.59; P = .01) and increase in exercise RV s′ indexed to PA pressure (0.09 cm·s−1/mm Hg; 95% CI, 0.02-0.16 cm·s−1/mm Hg; P = .01). Improvements in pulsatile RV load and RV-PA coupling were correlated with reduction in right atrial (RA) pressure (PA elastance Pearson r = 0.55; P =.008; RV s′/PA elastance Pearson r = −0.60; P =.002) and PCWP (PA elastance Pearson r = 0.58; P <.001; RV s′/PA elastance Pearson r = −0.47; P = .02). Dapagliflozin increased resistance-compliance time (dapagliflozin, median [IQR] change, 0.06 [0.03-0.15] seconds; placebo, median [IQR] change, 0.01 [−0.02 to 0.05] seconds; P =.046), resulting in higher PA compliance for any exercise pulmonary vascular resistance.Conclusions and RelevanceResults of this randomized clinical trial reveal that treatment with dapagliflozin for 24 weeks reduced pulsatile pulmonary vascular load and enhanced dynamic RV-PA interaction during exercise in patients with HFpEF, findings that are related to the magnitude of PCWP reduction. Benefits on dynamic right ventricular–pulmonary vascular coupling may partially explain the benefits of SGLT2 inhibitors in HFpEF.Trial RegistrationClinicalTrials.gov Identifier: NCT04730947

Abstract Aims The diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging based on resting assessments. Exercise echocardiography is often used to unmask abnormalities that develop during exercise, but the diagnostic criteria have not been standardized. This study aimed to elucidate how cardiologists utilize exercise echocardiography to diagnose HFpEF in real-world practice. Methods and results An international web-based survey involving 87 cardiologists was performed. We also performed a retrospective cross-sectional study to investigate the impact of different exercise echocardiographic diagnostic criteria in 652 dyspnoeic patients who underwent exercise echocardiography. The HFA-PEFF algorithm was the most commonly used exercise echocardiography criterion for HFpEF diagnoses (48%), followed by the ASE/EACVI criteria (24%) and other combinations of multiple parameters (22%). Among 652 patients, the proportion of HFpEF diagnosis varied substantially according to the criteria used ranging from 20.1% (ASE/EACVI criteria) to 44.3% (HFA-PEFF algorithm). Many cases (49.4–70.5%) remained indeterminate after exercise echocardiography, but only 41% of surveyed cardiologists would utilize exercise right heart catheterization to resolve an indeterminate result. Despite these diagnostic uncertainties, 54% of surveyed cardiologists would utilize exercise echocardiography results to initiate sodium–glucose co-transporter 2 inhibitors. Conclusion In real-world practice, exercise echocardiographic criteria utilized across cardiologists vary, which meaningfully impacts the frequency of HFpEF diagnoses, with indeterminate results being common. Despite these diagnostic uncertainties, many cardiologists initiate pharmacotherapy based on exercise echocardiography. The lack of consensus on universal diagnostic criteria for exercise echocardiography and approaches to indeterminate results may limit the delivery of evidence-based treatment for HFpEF.

Abstract 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.

Introduction: Reduced peak oxygen consumption (VO 2 ) is common and associated with adverse outcomes in patients with heart failure (HF) and preserved ejection fraction (HFpEF). According to the Fick principle, VO 2 is equal to the product of cardiac output (CO) and arterial-venous O 2 difference (AVO 2 diff). Patients with HFpEF display abnormalities each component, but no study has yet evaluated their prognostic impacts. Methods: Patients with HFpEF (n=501) and controls without HF (n=207) underwent invasive hemodynamic exercise testing with expired gas analysis and clinical follow up for the composite event of HF hospitalization or death. Results: Compared to controls, patients with HFpEF displayed slightly lower CO at rest with higher pulmonary capillary wedge pressure (PCWP). On exercise, subjects with HFpEF displayed blunted increases in CO and greater increase in PCWP (Figure A). As compared with controls, the slope of the increase in CO relative to VO 2 was lower in HFpEF (6.4 ± 3.3 vs 5.4 ± 3.2 L/L; P =0.0004), while augmentation in AVO 2 diff relative to VO 2 was greater in HFpEF (7.7 ± 5.4 vs 10.0 ± 5.6 min/dL; P <0.0001). Over a median 2.8 (1.1-4.6) years of follow up, 101 patients experienced the composite event. Patients with CO reserve below the median and increases in AVO 2 diff below median displayed higher risk of the composite endpoint (Figure B-C). After adjustments for age, sex, BMI, atrial fibrillation, LV mass, and EF, CO reserve remained strongly associated with the primary outcome (HR [95%CI] = 0.51 [0.38-0.68]; P <0.0001, per 1 SD increase) and the change of AVO 2 diff remained significant, but was less predictive (HR [95%CI] = 0.74 [0.60-0.92]; P =0.007, per 1 SD increase) in patients with HFpEF. Conclusions: Impaired ability to augment CO and peripheral O 2 delivery are associated with increasing risk of adverse events in HFpEF. Further study is required to identify therapeutic interventions targeting these hemodynamic perturbations to improve outcomes in HFpEF.

Introduction: Many patients with heart failure with preserved ejection fraction (HFpEF) display normal N-terminal-pro-B type natriuretic peptide (NTproBNP)levels. Mortality and hospitalization rates are lower in this group compared to patients with high NTproBNP, but it remains unclear whether these patients represent a fundamentally different phenotype or an earlier stage of disease. Methods: 213 subjects with HFpEF defined by invasive hemodynamics underwent serial echocardiographic examinations &gt;1 year apart. Clinical, cardiac structural, functional, and hemodynamic characteristics were examined. Results: Exam 2 was performed a median of 3.2 years (IQR 2.2-5.1) following Exam 1. From this cohort, 66 (33%) displayed normal NT-proBNP levels (≤125pg/ml, nBNP) and 147 (67%) displayed high NTproBNP (hBNP). Compared to hBNP, nBNP patients were younger (62±10 vs 71±9 years, p&lt;0.0001) and more obese (35±8 vs 32±7 kg/m 2 , p=0.005). At Exam 1, approximately 50% of nBNP displayed left ventricular (LV) systolic dysfunction defined as LV longitudinal strain (GLS)&lt;16% ( Figure A ) and LA dysfunction defined as left atrial (LA) reservoir strain&lt;26% ( Figure B ), but right ventricular (RV) systolic function as relatively preserved ( Figure C ). At Exam 2, LV, LA, and RV strain decreased in both groups (Panels A-C), with no difference between nBNP and hBNP in the velocity of change (p&gt;0.6 for all). More patients crossed the threshold definition for LV systolic and LA dysfunction in nBNP compared to hBNP ( Figure D and E ), but the prevalence of RV dysfunction increased more in hBNP ( Figure F ). Conclusions: In patients with HFpEF with normal NT-proBNP, biventricular systolic function and LA function deteriorate over time at similar pace. These data suggest that patients with HFpEF are not a fundamentally different disorder, but rather represent an earlier stage of disease that progresses from LV and LA dysfunction in early stages to RV dysfunction in advanced stages.

Abstract Aims We aimed to clarify the extent to which cardiac and peripheral impairments to oxygen delivery and utilization contribute to exercise intolerance and risk for adverse events, and how this relates to diversity and multiplicity in pathophysiologic traits. Methods and results Individuals with heart failure with preserved ejection fraction (HFpEF) and non-cardiac dyspnoea (controls) underwent invasive cardiopulmonary exercise testing and clinical follow-up. Haemodynamics and oxygen transport responses were compared. HFpEF patients were then categorized a priori into previously-proposed, non-exclusive descriptive clinical trait phenogroups, including cardiometabolic, pulmonary vascular disease, left atrial myopathy, and vascular stiffening phenogroups based on clinical and haemodynamic profiles to contrast pathophysiology and clinical risk. Overall, patients with HFpEF (n = 643) had impaired cardiac output reserve with exercise (2.3 vs. 2.8 L/min, p = 0.025) and greater reliance on peripheral oxygen extraction augmentation (4.5 vs. 3.8 ml/dl, p &lt; 0.001) compared to dyspnoeic controls (n = 219). Most (94%) patients with HFpEF met criteria for at least one clinical phenogroup, and 67% fulfilled criteria for multiple overlapping phenogroups. There was greater impairment in peripheral limitations in the cardiometabolic group and greater cardiac output limitations and higher pulmonary vascular resistance during exertion in the other phenogroups. Increasing trait multiplicity within a given patient was associated with worse exercise haemodynamics, poorer exercise capacity, lower cardiac output reserve, and greater risk for heart failure hospitalization or death (hazard ratio 1.74, 95% confidence interval 1.08–2.79 for 0–1 vs. ≥2 phenogroup traits present). Conclusions Though cardiac output response to exercise is limited in patients with HFpEF compared to those with non-cardiac dyspnoea, the relative contributions of cardiac and peripheral limitations vary with differing numbers and types of clinical phenotypic traits present. Patients fulfilling criteria for greater multiplicity and diversity of HFpEF phenogroup traits have poorer exercise capacity, worsening haemodynamic perturbations, and greater risk for adverse outcome.