mPAP/CO Slope and Oxygen Uptake Add Prognostic Value in Aortic Stenosis.

BACKGROUND: Recent guidelines redefined exercise pulmonary hypertension as a mean pulmonary artery pressure/cardiac output (mPAP/CO) slope >3 mm Hg·L-1·min-1. A peak systolic pulmonary artery pressure >60 mm Hg during exercise has been associated with an increased risk of cardiovascular death, heart failure rehospitalization, and aortic valve replacement in aortic valve stenosis. The prognostic value of the mPAP/CO slope in aortic valve stenosis remains unknown. METHODS: In this prospective cohort study, consecutive patients (n=143; age, 73±11 years) with an aortic valve area ≤1.5 cm2 underwent cardiopulmonary exercise testing with echocardiography. They were subsequently evaluated for the occurrence of cardiovascular events (ie, cardiovascular death, heart failure hospitalization, new-onset atrial fibrillation, and aortic valve replacement) during a follow-up period of 1 year. Findings were externally validated (validation cohort, n=141). RESULTS: One cardiovascular death, 32 aortic valve replacements, 9 new-onset atrial fibrillation episodes, and 4 heart failure hospitalizations occurred in the derivation cohort, whereas 5 cardiovascular deaths, 32 aortic valve replacements, 1 new-onset atrial fibrillation episode, and 10 heart failure hospitalizations were observed in the validation cohort. Peak aortic velocity (odds ratio [OR] per SD, 1.48; P=0.036), indexed left atrial volume (OR per SD, 2.15; P=0.001), E/e' at rest (OR per SD, 1.61; P=0.012), mPAP/CO slope (OR per SD, 2.01; P=0.002), and age-, sex-, and height-based predicted peak exercise oxygen uptake (OR per SD, 0.59; P=0.007) were independently associated with cardiovascular events at 1 year, whereas peak systolic pulmonary artery pressure was not (OR per SD, 1.28; P=0.219). Peak Vo2 (percent) and mPAP/CO slope provided incremental prognostic value in addition to indexed left atrial volume and aortic valve area (P<0.001). These results were confirmed in the validation cohort. CONCLUSIONS: In moderate and severe aortic valve stenosis, mPAP/CO slope and percent-predicted peak Vo2 were independent predictors of cardiovascular events, whereas peak systolic pulmonary artery pressure was not. In addition to aortic valve area and indexed left atrial volume, percent-predicted peak Vo2 and mPAP/CO slope cumulatively improved risk stratification.

Rationale and Design of the DECONGEST (Diuretic Treatment in Acute Heart Failure With Volume Overload Guided by Serial Spot Urine Sodium Assessment) Study.

AIMS: To evaluate whether early-combination diuretic therapy guided by serial post-diuretic urine sodium concentration (UNa+) assessments in acute heart failure (AHF) facilitates safe and effective decongestion. METHODS: The Diuretic Treatment in Acute Heart Failure with Volume Overload Guided by Serial Spot Urine Sodium Assessment (DECONGEST) study is a pragmatic, 2-center, randomized, parallel-arm, open-label study aiming to enroll 104 patients with AHF and clinically evident fluid overload requiring treatment with intravenous loop diuretics. Patients are randomized to receive standard of care or a bundled approach comprising: (1) systematic post-diuretic UNa+ assessments until successful decongestion, defined as no remaining clinical signs of fluid overload with a post-diuretic UNa+ ≤ 80 mmol/L; (2) thrice-daily intravenous loop diuretic bolus therapy, with dosing according to estimated glomerular filtration rate; (3) upfront use of intravenous acetazolamide (500 mg once daily [OD]); and (4) full nephron blockade with high-dose oral chlorthalidone (100 mg OD) and intravenous canreonate (200 mg OD) for diuretic resistance, defined as persisting signs of fluid overload with a post-diuretic UNa+ ≤ 80 mmol/L. The primary endpoint of the DECONGEST study is a hierarchical composite of (1) survival at 30 days; (2) days alive and out of hospital or care facility up to 30 days; and (3) greater relative decrease in natriuretic peptide levels from baseline to day 30. CONCLUSION: The DECONGEST study aims to determine whether an intensive diuretic regimen focused on early combination therapy, guided by serial post-diuretic UNa+ assessments, safely enhances decongestion, warranting further evaluation in a larger trial powered for clinical events.

Heart failure with preserved ejection fraction: relevance of a dedicated dyspnoea clinic.

BACKGROUND AND AIMS: Heart failure with preserved ejection fraction (HFpEF) is a syndrome with a heterogeneous presentation. This study provides an in-;depth description of haemodynamic and metabolic alterations revealed by systematic assessment through cardiopulmonary exercise testing combined with exercise echocardiography (CPETecho) within a dedicated dyspnoea clinic. METHODS AND RESULTS: Consecutive patients (n = 297), referred to a dedicated dyspnoea clinic using a standardized workup including CPETecho, with HFpEF diagnosed through a H2FPEF score ≥6 or HFA-PEFF score ≥5, were evaluated. A median of four haemodynamic/metabolic alterations was uncovered per patient: impaired stroke volume reserve (73%), impaired chronotropic reserve (72%), exercise pulmonary hypertension (65%), and impaired diastolic reserve (64%) were the most frequent cardiac alterations. Impaired peripheral oxygen extraction and a ventilatory limitation were present in 40% and 39%, respectively. In 267 patients (90%), 575 further diagnostic examinations were recommended (median of two tests per patient). Cardiac magnetic resonance imaging, coronary or amyloidosis workup, ventilation-perfusion scanning, and pulmonology referral were each recommended in approximately one out of three patients. In 293 patients (99%), 929 cardiovascular drug optimizations were performed (median of 3 modifications per patient). In 110 patients (37%), 132 cardiovascular interventions were performed, with ablation as the most frequent procedure. CONCLUSION: Holistic workup of HFpEF patients within a multidisciplinary, dedicated dyspnoea clinic, including systematic implementation of CPETecho reveals various haemodynamic/metabolic alterations, leading to further diagnostic testing and potential treatment changes in the majority of cases.

Impact of continuous vs. interval training on oxygen extraction and cardiac function during exercise in type 2 diabetes mellitus.

PURPOSE: Exercise training improves exercise capacity in type 2 diabetes mellitus (T2DM). It remains to be elucidated whether such improvements result from cardiac or peripheral muscular adaptations, and whether these are intensity dependent. METHODS: 27 patients with T2DM [without known cardiovascular disease (CVD)] were randomized to high-intensity interval training (HIIT, n = 15) or moderate-intensity endurance training (MIT, n = 12) for 24 weeks (3 sessions/week). Exercise echocardiography was applied to investigate cardiac output (CO) and oxygen (O2) extraction during exercise, while exercise capacity [([Formula: see text] (mL/kg/min)] was examined via cardiopulmonary exercise testing at baseline and after 12 and 24 weeks of exercise training, respectively. Changes in glycaemic control (HbA1c and glucose tolerance), lipid profile and body composition were also evaluated. RESULTS: 19 patients completed 24 weeks of HIIT (n = 10, 66 ± 11 years) or MIT (n = 9, 61 ± 5 years). HIIT and MIT similarly improved glucose tolerance (pTime = 0.001, pInteraction > 0.05), [Formula: see text] (mL/kg/min) (pTime = 0.001, pInteraction > 0.05), and exercise performance (Wpeak) (pTime < 0.001, pInteraction > 0.05). O2 extraction increased to a greater extent after 24 weeks of MIT (56.5%, p1 = 0.009, pTime = 0.001, pInteraction = 0.007). CO and left ventricular longitudinal strain (LS) during exercise remained unchanged (pTime > 0.05). A reduction in HbA1c was correlated with absolute changes in LS after 12 weeks of MIT (r = - 0.792, p = 0.019, LS at rest) or HIIT (r = - 0.782, p = 0.038, LS at peak exercise). CONCLUSION: In patients with well-controlled T2DM, MIT and HIIT improved exercise capacity, mainly resulting from increments in O2 extraction capacity, rather than changes in cardiac output. In particular, MIT seemed highly effective to generate these peripheral adaptations. TRIAL REGISTRATION: NCT03299790, initially released 09/12/2017.

Predictors of poor outcome in critically ill patients with COVID-19 pneumonia treated with extracorporeal membrane oxygenation.

INTRODUCTION: We aimed to identify risk factors associated with ICU mortality in critically ill patients with COVID-19 pneumonia treated with Extracorporeal membrane oxygenation (ECMO). We also aimed to assess protocol violations of the local eligibility criteria of ECMO initiation. METHODS: All 31 consecutive adult patients with confirmed COVID-19 pneumonia admitted to ICU and treated with ECMO from March 13th 2020 to 8 December 2021 were enrolled. Eligibility criteria for ECMO initiation were: P/F-ratio<50 mmHg >3 hours, P/F-ratio<80 mmHg >6 hours or pH<7.25 + PaCO2>60 mmHg >6 hours, despite maximal protective invasive ventilation. Primary outcome was ICU mortality. Univariate logistic regression analyses were performed to identify predictors of ICU mortality. RESULTS: 12 out of 31 patients (38.7%) did not survive ECMO treatment in ICU. Half of the non-survivors suffered from acute kidney failure compared to 3 out of 19 survivors (15.79%) (p = .04). Half of the non-survivors required CRRT treatment versus 1 patient in the survivor group (5.3%) (p < .01). Higher age (2.45 (0.97-6.18), p = .05), the development of AKI (5.33 (1.00-28.43), p = .05), need of CRRT during ICU stay (18.00 (1.79-181.31), p = .01) and major bleeding during ECMO therapy (0.51 (0.19-0.89), p < .01) were identified to be predictors of ICU mortality. CONCLUSION: Almost 60% of patients could be treated successfully with ECMO with sustained results at 3 months. Predictors for ICU mortality were development of AKI and need of CRRT during ICU stay, higher age category and major bleeding. Inadvertent ECMO allocation was noted in almost one in five patients.

Iron Deficiency Is Associated With Impaired Biventricular Reserve and Reduced Exercise Capacity in Patients With Unexplained Dyspnea.

BACKGROUND: Iron deficiency (ID) is frequent and associated with diminished exercise capacity in heart failure (HF), but its contribution to unexplained dyspnea without a HF diagnosis at rest remains unclear. METHODS AND RESULTS: Consecutive patients with unexplained dyspnea and normal echocardiography and pulmonary function tests at rest underwent prospective standardized cardiopulmonary exercise testing with echocardiography in a tertiary care dyspnea clinic. ID was defined as ferritin of <300 µg/L and a transferrin saturation of <20% and its impact on peak oxygen uptake (peakVO2), biventricular response to exercise, and peripheral oxygen extraction was assessed. Of 272 patients who underwent cardiopulmonary exercise testing with echocardiography, 63 (23%) had ID. For a similar respiratory exchange ratio, patients with ID had lower peakVO2 (14.6 ± 7.6 mL/kg/minvs 17.8 ± 8.8 mL/kg/min; P = .009) and maximal workload (89 ± 50 watt vs 108 ± 56 watt P = .047), even after adjustment for the presence of anemia. At rest, patients with ID had a similar left ventricular and right ventricular (RV) contractile function. During exercise, patients with ID had lower cardiac output reserve (P < .05) and depressed RV function by tricuspid s' (P = .004), tricuspid annular plane systolic excursion (P = .034), and RV end-systolic pressure-area ratio (P = .038), with more RV-pulmonary artery uncoupling measured by tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure ratio (P = .023). RV end-systolic pressure-area ratio change from rest to peak exercise, as a load-insensitive metric of RV contractility, was lower in patients with ID (2.09 ± 0.72 mm Hg/cm2 vs 2.58 ± 1.14 mm Hg/cm2; P < .001). ID was associated with impaired peripheral oxygen extraction (peakVO2/peak cardiac output; P = .036). Cardiopulmonary exercise testing with echocardiography resulted in a diagnosis of HF with preserved ejection fraction in 71 patients (26%) based on an exercise E/e' ratio of >14, with equal distribution in patients with (28.6%) or without ID (25.4%, P = .611). None of these findings were influenced in a sensitivity analysis adjusted for a final diagnosis of HFpEF as etiology for the unexplained dyspnea. CONCLUSIONS: In patients with unexplained dyspnea without clear HF at rest, ID is common and associated with decreased exercise capacity, diminished biventricular contractile reserve, and decreased peripheral oxygen extraction.

Asymptomatic type 2 diabetes mellitus display a reduced myocardial deformation but adequate response during exercise.

BACKGROUND AND PURPOSE: The development of myocardial fibrosis is a major complication of Type 2 diabetes mellitus (T2DM), impairing myocardial deformation and, therefore, cardiac performance. It remains to be established whether abnormalities in longitudinal strain (LS) exaggerate or only occur in well-controlled T2DM, when exposed to exercise and, therefore, cardiac stress. We therefore studied left ventricular LS at rest and during exercise in T2DM patients vs. healthy controls. METHODS AND RESULTS: Exercise echocardiography was applied with combined breath-by-breath gas exchange analyses in asymptomatic, well-controlled (HbA1c: 6.9 ± 0.7%) T2DM patients (n = 36) and healthy controls (HC, n = 23). Left ventricular LS was assessed at rest and at peak exercise. Peak oxygen uptake (V̇O2peak) and workload (Wpeak) were similar between groups (p > 0.05). Diastolic (E, e's, E/e') and systolic function (left ventricular ejection fraction) were similar at rest and during exercise between groups (p > 0.05). LS (absolute values) was significantly lower at rest and during exercise in T2DM vs. HC (17.0 ± 2.9% vs. 19.8 ± 2% and 20.8 ± 4.0% vs. 23.3 ± 3.3%, respectively, p < 0.05). The response in myocardial deformation (the change in LS from rest up to peak exercise) was similar between groups (+ 3.8 ± 0.6% vs. + 3.6 ± 0.6%, in T2DM vs. HC, respectively, p > 0.05). Multiple regression revealed that HDL-cholesterol, fasted insulin levels and exercise tolerance accounted for 30.5% of the variance in response of myocardial deformation in the T2DM group (p = 0.002). CONCLUSION: Myocardial deformation is reduced in well-controlled T2DM and despite adequate responses, such differences persist during exercise. TRIAL REGISTRATION: NCT03299790, initially released 09/12/2017.

Complicated Infective Endocarditis of a Mechanical Aortic Valve due to Propionibacterium acnes.

Propionibacterium acnes is known to be a causative microorganism in low-grade and late prosthetic valve endocarditis. Here, the case is reported of a late, apparently culture-negative endocarditis of an aortic mechanical prosthesis, diagnosed to be caused by P. acnes after pan-bacterial polymerase chain reaction (PCR) on the explanted mechanical prosthetic valve. This endocarditis was complicated by an aortic root abscess; after surgical resection a ventricular septal defect (VSD) with overt right ventricular and multiple organ failure occurred. Low suspicion, the failure of routine blood culture to grow P. acnes and erroneous interpretation of P. acnes as contamination, frequently delay the correct diagnosis and treatment of this condition. Hence, although infection with P. acnes is usually indolent, abscess formation and a need for surgery are common.

Exercise-Induced Pulmonary Hypertension: Rationale for Correcting Pressures for Flow and Guide to Non-Invasive Diagnosis.

Exercise-induced pulmonary hypertension (exPHT) is a hemodynamic condition linked to increased morbidity and mortality across various cardiopulmonary diseases. Traditional definitions of exPHT rely on absolute cut-offs, such as mean pulmonary artery pressure (mPAP) above 30 mmHg during exercise. However, recent research suggests that these cut-offs may not accurately reflect pathophysiological changes, leading to false positives and false negatives. Instead, the mPAP over cardiac output (CO) slope, which incorporates both pressure and flow measurements, has emerged as a more reliable indicator. A slope exceeding 3 mmHg/L/min is now considered diagnostic for exPHT and strongly correlates with adverse outcomes. Stress echocardiography serves as a viable alternative to invasive assessment, enabling broader implementation. This review discusses the physiological basis of pulmonary hemodynamics during exercise, the advantages of the mPAP/CO slope over absolute pressure measurements, the evidence supporting its inclusion in clinical guidelines, and provides a practical guide for non-invasive determining the mPAP/CO slope in clinical practice.

Non-invasive imaging in acute decompensated heart failure with preserved ejection fraction.

Non-invasive imaging plays an increasingly important role in emergency medicine, given the trend towards smaller, portable ultrasound devices, the integration of ultrasound imaging across diverse medical disciplines, and the growing evidence supporting its clinical benefits for the patient. Heart failure with preserved ejection fraction (HFpEF) provides a compelling illustration of the impactful role that imaging plays in distinguishing diverse clinical presentations of heart failure with numerous associated comorbidities, including pulmonary, renal, or hepatic diseases. While a preserved left ventricular ejection fraction might misguide the clinician away from diagnosing cardiac disease, there are several clues provided by cardiac, vascular, and lung ultrasonography, as well as other imaging modalities, to rapidly identify (decompensated) HFpEF. Congestion remains the primary reason why patients with heart failure (irrespective of ejection fraction) seek emergency care. Furthermore, comprehensive phenotyping is becoming increasingly important, considering the development of targeted treatments for conditions exhibiting HFpEF physiology, such as cardiac amyloidosis. Timely recognition in such cases has lasting implications for long-term outcomes.

Cardiac dysfunction rather than aortic valve stenosis severity drives exercise intolerance and adverse haemodynamics.

AIMS: To study the impact of heart failure with preserved ejection fraction (HFpEF) vs. aortic stenosis (AS) lesion severity on left ventricular (LV) hypertrophy, diastolic dysfunction, left atrial (LA) dysfunction, haemodynamics, and exercise capacity. METHODS AND RESULTS: Patients (n = 206) with at least moderate AS (aortic valve area ≤0.85 cm/m2) and discordant symptoms underwent cardiopulmonary exercise testing with simultaneous echocardiography. The population was stratified according to the probability of underlying HFpEF by the heavy, hypertension, atrial fibrillation, pulmonary hypertension, elder, filling pressure (H2FPEF) score [0-5 (AS/HFpEF-) vs. 6-9 points (AS/HFpEF+)] and AS severity (Moderate vs. Severe). Mean age was 73 ± 10 years with 40% women. Twenty-eight patients had Severe AS/HFpEF+ (14%), 111 Severe AS/HFpEF- (54%), 13 Moderate AS/HFpEF+ (6%), and 54 Moderate AS/HFpEF- (26%). AS/HFpEF+ vs. AS/HFpEF- patients, irrespective of AS severity, had a lower LV global longitudinal strain, impaired diastolic function, reduced LV compliance, and more pronounced LA dysfunction. The pulmonary arterial pressure-cardiac output slope was significantly higher in AS/HFpEF+ vs. AS/HFpEF- (5.4 ± 3.1 vs. 3.9 ± 2.2 mmHg/L/min, respectively; P = 0.003), mainly driven by impaired cardiac output and chronotropic reserve, with signs of right ventricular pulmonary arterial uncoupling. AS/HFpEF+ vs. AS/HFpEF- was associated with a lower peak aerobic capacity (11.5 ± 3.7 vs. 15.9 ± 5.9 mL/min/kg, respectively; P < 0.0001) but did not differ between Moderate and Severe AS (14.7 ± 5.5 vs. 15.2 ± 5.9 mL/min/kg, respectively; P = 0.6). CONCLUSION: A high H2FPEF score is associated with a reduced exercise capacity and adverse haemodynamics in patients with moderate to severe AS. Both exercise performance and haemodynamics correspond better with intrinsic cardiac dysfunction than AS severity.

Exercise pulmonary hypertension by the mPAP/CO slope in primary mitral regurgitation.

AIMS: Exercise-induced pulmonary hypertension (PH), defined by a mean pulmonary arterial pressure over cardiac output (mPAP/CO) slope >3 mmHg/L/min, has important diagnostic and prognostic implications. The aim of this study is to investigate the value of the mPAP/CO slope in patients with more than moderate primary mitral regurgitation (MR) with preserved ejection fraction and no or discordant symptoms. METHODS AND RESULTS: A total of 128 consecutive patients were evaluated with exercise echocardiography and cardiopulmonary testing. Clinical outcome was defined as the composite of mitral valve intervention, new-onset atrial fibrillation, cardiovascular hospitalization, and all-cause mortality. The mean age was 63 years, 61% were male, and the mean LVEF was 66 ± 6%. The mPAP/CO slope correlated with peak VO2 (r = -0.52, P < 0.001), while the peak systolic pulmonary artery pressure (sPAP) did not (r = -0.06, P = 0.584). Forty-six per cent (n = 59) had peak exercise sPAP ≥60 mmHg, and 37% (n = 47) had mPAP/CO slope >3 mmHg/L/min. Event-free survival was 55% at 1 year and 46% at 2 years, with reduced survival in patients with mPAP/CO slope >3 mmHg/L/min (hazard ratio, 4.9; 95% confidence interval, 2.9-8.2; P < 0.001). In 53 cases (41%), mPAP/CO slope and peak sPAP were discordant: patients with slope >3 mmHg/L/mmHg and sPAP <60 mmHg (n = 21) had worse outcome vs. peak sPAP ≥60 mmHg and normal slope (n = 32, log-rank P = 0.003). The mPAP/CO slope improved predictive models for outcome, incremental to resting and exercise sPAP, and peak VO2. CONCLUSION: Exercise PH defined by the mPAP/CO slope >3 mmHg/L/min is associated with decreased exercise capacity and a higher risk of adverse events in significant primary MR and no or discordant symptoms. The slope provides a greater prognostic value than single sPAP measures and peak VO2.

Mitral regurgitation in heart failure with preserved ejection fraction: The interplay of valve, ventricle, and atrium.

Mitral regurgitation (MR) is highly prevalent among patients with heart failure and preserved ejection fraction (HFpEF). Despite this combination being closely associated with unfavourable outcomes, it remains relatively understudied. This is partly due to the inherent heterogeneity of patients with HFpEF. To address this gap, dissecting HFpEF into mechanism-based phenotypes may offer a promising avenue for advancing our comprehension of these complex intertwined conditions. This review employs the validated CircAdapt model to explore the haemodynamic implications of moderate to severe MR across a well-defined spectrum of myocardial disease, characterized by impaired relaxation and reduced myocardial compliance. Both heart failure and mitral valve disease share overlapping symptomatology, primarily attributed to elevated pulmonary pressures. The intricate mechanisms contributing to these elevated pressures are multifaceted, potentially influenced by diastolic dysfunction, left atrial myopathy, and MR. Accurate evaluation of the haemodynamic and clinical impact of MR necessitates a comprehensive approach, taking into account the characteristics of both the left atrium and left ventricle, as well as their intricate interactions, which may currently be underemphasized in diagnostic practice. This holistic assessment is imperative for enhancing our understanding and refining therapeutic strategies within this patient cohort.

The Oxygen Cascade According to HFpEF Likelihood: A Focus on Sex Differences.

Background: Women are at greater risk for heart failure with preserved ejection fraction (HFpEF). Objectives: The aim of the study was to compare sex differences in the pathophysiology of exertional breathlessness in patients with high vs low HFpEF likelihood. Methods: This cohort study evaluated consecutive patients (n = 1,936) with unexplained dyspnea using cardiopulmonary exercise testing and simultaneous echocardiography and quantified peak oxygen uptake (peak VO2) and its determinants. HFpEF was considered likely when the H2FPEF or HFA-PEFF score was ≥6 or ≥5, respectively. Sex differences were evaluated with the Student's t-test or Mann-Whitney U test and determinants of exercise capacity with a multivariable linear regression. Results: The cohort included 1,963 patients (49% women and 28% [n = 555] with a high HFpEF likelihood). HFpEF likelihood did not impact the magnitude of sex differences in peak VO2 and its determinants. Overall, women had lower peak VO2 (mean difference -4.4 mL/kg/min [95% CI: -3.7 to -5.1 mL/kg/min]) secondary to a reduced O2 delivery (-0.5 L/min [95% CI: -0.4 to -0.6 L/min]) and less oxygen extraction (-2.9 mL/dL [95% CI: -2.5 to -3.2 mL/dL]). Reduced O2 delivery was due to lower hemoglobin (-1.2 g/dL [95% CI: -0.9 to -1.5 g/dL]) and smaller stroke volume (-15 mL [95% CI: -14 to -17 mL]). Women demonstrated increased mean pulmonary artery pressure/cardiac output slope (+0.5 mm Hg/L/min [95% CI: 0.3-0.7 mm Hg/L/min]) and left ventricular ejection fraction (+1% [95% CI: 1%-2%]), while they had smaller left ventricular end-diastolic volumes (-9 mL/m2 [95% CI: -8 to -11 mL/m2]) and mass (-12 g/m2 [95% CI: -9 to -14 g/m2]) and more often iron deficiency (55% vs 33%; P < 0.001). Conclusions: Women with unexplained dyspnea had significantly lower peak VO2, regardless of HFpEF likelihood, attributed to both lower peak exercise O2 delivery and extraction. This suggests that physiologic sex differences, and not HFpEF likelihood, are an important factor contributing to functional limitations in females with exertional breathlessness.

Clinical Significance of Exercise Pulmonary Hypertension With a Negative Diastolic Stress Test for Suspected Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Half of patients with heart failure with preserved ejection fraction (HFpEF) remain undiagnosed by resting evaluation alone. Therefore, exercise testing is proposed. The diastolic stress test (DST), however, has limited sensitivity. We aimed to determine the clinical significance of adding the mean pulmonary artery pressure over cardiac output (mPAP/CO) slope to the DST in suspected HFpEF. METHODS AND RESULTS: In this prospective cohort study, consecutive patients (n=1936) with suspected HFpEF underwent exercise echocardiography with simultaneous respiratory gas analysis. These patients were stratified by exercise E over e' (exE/e') and mPAP/CO slope, and peak oxygen uptake, natriuretic peptides (NT-proBNP [N-terminal pro-B-type natriuretic peptide]), and score-based HFpEF likelihood were compared. Twenty-two percent of patients (n=428) had exE/e'<15 despite a mPAP/CO slope>3 mm Hg/L per min, 24% (n=464) had a positive DST (exE/e'≥15), and 54% (n=1044) had a normal DST and slope. Percentage of predicted oxygen uptake was similar in the group with exE/e'<15 but high mPAP/CO slope and the positive DST group (-2% [-5% to +1%]), yet worse than in those with normal DST and slope (-12% [-14% to -9%]). Patients with exE/e'<15 but a high slope had NT-proBNP levels and H2FPEF (heavy, hypertensive, atrial fibrillation, pulmonary hypertension, elder; filling pressure) scores intermediate to the positive DST group and the group with both a normal DST and slope. CONCLUSIONS: Twenty-two percent of patients with suspected HFpEF presented with a mPAP/CO slope>3 mm Hg/L per min despite a negative DST. These patients had HFpEF characteristics and a peak oxygen uptake as low as patients with a positive DST. Therefore, an elevated mPAP/CO slope might indicate HFpEF irrespective of the DST result.

Generalized Pairwise Comparisons to Assess Treatment Effects: JACC Review Topic of the Week.

A time-to-first-event composite endpoint analysis has well-known shortcomings in evaluating a treatment effect in cardiovascular clinical trials. It does not fully describe the clinical benefit of therapy because the severity of the events, events repeated over time, and clinically relevant nonsurvival outcomes cannot be considered. The generalized pairwise comparisons (GPC) method adds flexibility in defining the primary endpoint by including any number and type of outcomes that best capture the clinical benefit of a therapy as compared with standard of care. Clinically important outcomes, including bleeding severity, number of interventions, and quality of life, can easily be integrated in a single analysis. The treatment effect in GPC can be expressed by the net treatment benefit, the success odds, or the win ratio. This review provides guidance on the use of GPC and the choice of treatment effect measures for the analysis and reporting of cardiovascular trials.

Pulmonary hypertension during exercise underlies unexplained exertional dyspnoea in patients with Type 2 diabetes.

AIMS: To compare the cardiac function and pulmonary vascular function during exercise between dyspnoeic and non-dyspnoeic patients with Type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: Forty-seven T2DM patients with unexplained dyspnoea and 50 asymptomatic T2DM patients underwent exercise echocardiography combined with ergospirometry. Left ventricular (LV) function [stroke volume, cardiac output (CO), LV ejection fraction, systolic annular velocity (s')], estimated LV filling pressures (E/e'), mean pulmonary arterial pressures (mPAPs) and mPAP/COslope were assessed at rest, low- and high-intensity exercise with colloid contrast. Groups had similar patient characteristics, glycemic control, stroke volume, CO, LV ejection fraction, and E/e' (P > 0.05). The dyspnoeic group had significantly lower systolic LV reserve at peak exercise (s') (P = 0.021) with a significant interaction effect (P < 0.001). The dyspnoeic group also had significantly higher mPAP and mPAP/CO at rest and exercise (P < 0.001) with significant interaction for mPAP (P < 0.009) and insignificant for mPAP/CO (P = 0.385). There was no significant difference in mPAP/COslope between groups (P = 0.706). However, about 61% of dyspnoeic vs. 30% of non-dyspnoeic group had mPAP/COslope > 3 (P = 0.009). The mPAP/COslope negatively predicted V̇O2peak in dyspneic group (ß = -1.86, 95% CI: -2.75, -0.98; multivariate model R2:0.54). CONCLUSION: Pulmonary hypertension and less LV systolic reserve detected by exercise echocardiography with colloid contrast underlie unexplained exertional dyspnoea and reduced exercise capacity in T2DM.

Cardiopulmonary Exercise Testing with Echocardiography to Identify Mechanisms of Unexplained Dyspnea.

Little data is available about the pathophysiological mechanisms of unexplained dyspnea and their clinical meaning. Consecutive patients with unexplained dyspnea underwent prospective standardized cardiopulmonary exercise testing with echocardiography (CPETecho). Patients were grouped as having normal exercise capacity (peak VO2 > 80% with respiratory exchange [RER] > 1.05), reduced exercise capacity (peak VO2 ≤ 80% with RER > 1.05), or a submaximal exercise test (RER ≤ 1.05). From 307 patients, 144 (47%) had normal and 116 (38%) reduced exercise capacity, and 47 (15%) had a submaximal exercise test. Patients with reduced versus normal exercise capacity had significantly more mechanisms for unexplained dyspnea (2.3±1.0 vs 1.5±1.0, respectively; p<0.001). Exercise PH (42%), low heart rate reserve (51%), low stroke volume reserve (38%), low diastolic reserve (18%), and peripheral muscle limitation (17%) were most common. Patients with more mechanisms for dyspnea displayed poorer peak VO2 and had an increased risk for cardiovascular hospitalization (p=0.002). Patients with unexplained dyspnea display multiple coexisting mechanisms for exercise intolerance, which relate to the severity of exercise limitation and risk of subsequent cardiovascular hospitalizations.

Exercise Systolic Reserve and Exercise Pulmonary Hypertension Improve Diagnosis of Heart Failure With Preserved Ejection Fraction.

AIMS: Diastolic stress testing (DST) is recommended to confirm heart failure with preserved ejection fraction (HFpEF) in patients with exertional dyspnea, but current algorithms do not detect all patients. We aimed to identify additional echocardiographic markers of elevated pulmonary arterial wedge pressure during exercise (exPAWP) in patients referred for DST. METHODS AND RESULTS: We identified candidate parameters in 22 patients referred for exercise right heart catheterization with simultaneous echocardiography. Elevated exPAWP (≥25 mmHg) was present in 14 patients, and was best identified by peak septal systolic annular velocity <9.5 cm/s [exS', area under the receiver operating characteristic curve (AUC) 0.97, 95% confidence interval 0.92-1.0] and mean pulmonary artery pressure/cardiac output slope ≥3.2 mmHg/L [mPAP/CO, AUC 0.88 (0.72-1.0)]. We propose a decision tree to identify patients with elevated exPAWP. Applying this decision tree to 326 patients in an independent non-invasive DST cohort showed that patients labeled as "high probability of HFpEF" (n = 85) had reduced peak oxygen uptake [13.0 (10.7-15.1) mL/kg/min, p < 0.001 vs. intermediate/low probability], high H2FPEF score [53 (40-72) %, p < 0.001 vs. intermediate/low probability], and typical clinical characteristics. The diagnostic yield of DST increased from 11% using exercise E/e', to 62% using the decision tree. CONCLUSION: In DST for suspected HFpEF, exS' was the most accurate echocardiographic parameter to identify elevated PAWP. We propose a decision tree including exS' and mPAP/CO for interpretation of DST. Application of this decision tree revealed typical HFpEF characteristics in patients labeled as high probability of HFpEF, and substantially reduced the number of inconclusive results.