Obokata, Masaru

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.

BACKGROUND: Plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) is commonly used to diagnose heart failure with preserved ejection fraction (HFpEF), but its diagnostic performance in the ambulatory/outpatient setting is unknown because previous studies lacked objective reference standards. METHODS: Among patients with chronic dyspnea, diagnosis of HFpEF or noncardiac dyspnea was determined conclusively by exercise catheterization in a derivation cohort (n=414), multicenter validation cohort 1 (n=560), validation cohort 2 (n=207), and a nonobese Japanese validation cohort 3 (n=77). Optimal NT-proBNP cut points for HFpEF rule out (optimizing sensitivity) and rule in (optimizing specificity) were derived and tested, stratified by obesity and atrial fibrillation. Derived cut points were tested in 3 additional validation cohorts (cohorts 4–6) in whom HFpEF was diagnosed by resting catheterization only (n=260), previous hospitalization for heart failure (n=447), or exercise echocardiography (n=517), respectively. RESULTS: Current recommended rule-out NT-proBNP threshold <125 pg/mL had 82% sensitivity (95% CI, 77%–88%) with a body mass index (BMI) <35 kg/m 2 , decreasing to 67% (95% CI, 58%–77%) with a BMI ≥35 kg/m 2 . A lower rule-out NT-proBNP threshold <50 pg/mL displayed good sensitivity with a BMI <35 kg/m 2 (97% [95% CI, 95%–99%]), with a modest decline in sensitivity with a BMI ≥35 kg/m 2 (86% [95% CI, 79%–93%]); diagnostic thresholds were confirmed in validation cohorts 1 and 2 (91% [95% CI, 88%–95%] and 86% [95% CI, 80%–93%] with a BMI <35 kg/m 2 ; 80% [95% CI, 74%–87%] and 84% [95% CI, 74%–93%] with a BMI ≥35 kg/m 2 ). Current consensus age- and BMI-stratified rule-in thresholds demonstrated only 65% specificity (95% CI, 57%–72%). Rule-in NT-proBNP threshold ≥500 pg/mL had 85% specificity (95% CI, 78%–91%) with a BMI <35 kg/m 2 (87% [95% CI, 80%–94%] and 90% [95% CI, 81%–99%] in validation cohorts), with 100% specificity at a BMI ≥35 kg/m 2 (93% [95% CI, 81%–100%] and 100% in validation cohorts). With a BMI ≥35 kg/m 2 , lower rule-in thresholds (≥220 pg/mL) provided good specificity (88% [95% CI, 73%–100%]; 93% [95% CI, 81%–100%] and 100% in validation cohorts). Findings were consistent in validation cohorts 3 through 6 (sensitivity of <50 pg/mL, 93%–98%; specificity of ≥500 pg/mL, 82%–89%). NT-proBNP provided no incremental discrimination among patients with history of AF; ≥98% of patients with AF and dyspnea were found to have HFpEF in our cohorts. CONCLUSIONS: In patients with chronic unexplained dyspnea, current rule-in and rule-out NT-proBNP diagnostic thresholds lead to unacceptably high error rates, with important interactions by obesity and AF status. In our study, NT-proBNP provided little value in those with AF and dyspnea because the presence of AF is by itself a robust biomarker of HFpEF. Use of separate rule-in and rule-out diagnostic thresholds stratified by BMI reduces miscategorization and can guide more appropriate use of exercise testing for possible HFpEF.

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.

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 Aim Left atrial (LA) myopathy is increasingly recognized as an important phenotypic trait in heart failure (HF) with preserved ejection fraction (HFpEF). Right atrial (RA) remodelling and dysfunction also develop in HFpEF, but little data are available regarding the clinical characteristics and pathophysiology among patients with isolated LA, RA, or biatrial myopathy. Methods and results Patients with HFpEF underwent invasive haemodynamic exercise testing, comprehensive imaging including speckle tracking strain echocardiography, and clinical follow-up at Mayo Clinic between 2006 and 2018. LA myopathy was defined as LA volume index &gt;34 ml/m2 and/or LA reservoir strain ≤24% and RA myopathy by RA volume index &gt;39 ml/m2 in men and &gt;33 ml/m2 in women and/or RA reservoir strain ≤19.8%. Of 476 consecutively evaluated patients with HFpEF defined by invasive exercise testing with evaluable atrial structure/function, 125 (26%) had no atrial myopathy, 147 (31%) had isolated LA myopathy, 184 (39%) had biatrial myopathy, and 20 (4%) had isolated RA myopathy. Patients with HFpEF and biatrial myopathy had more atrial fibrillation, poorer left ventricular systolic and diastolic function, more severe pulmonary vascular disease, tricuspid regurgitation, ventricular interdependence and right ventricular dysfunction, and poorer cardiac output reserve with exercise. There were 94 patients with events over a median follow-up of 2.9 (interquartile range 1.4–4.6) years. Individuals with biatrial myopathy had an 84% higher risk of HF hospitalization or death as compared to those with isolated LA myopathy (hazard ratio 1.84; 95% confidence interval 1.16–2.92, p = 0.01). Conclusions Biatrial myopathy identifies patients with more advanced HFpEF characterized by more severe pulmonary vascular disease, right HF, poorer cardiac reserve, and a greater risk for adverse outcomes. Further study is required to define optimal strategies to treat and prevent biatrial myopathy in HFpEF.