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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 cm 2 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 Vo 2 (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 Vo 2 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 Vo 2 and mPAP/CO slope cumulatively improved risk stratification., Competing Interests: Disclosures None.

Aims: Degenerative aortic valve stenosis with preserved ejection fraction (ASpEF) and heart failure with preserved ejection fraction (HFpEF) display intriguing similarities. This study aimed to provide a non-invasive, comparative analysis of ASpEF versus HFpEF at rest and during exercise., Methods and Results: We prospectively enrolled 148 patients with HFpEF and 150 patients with degenerative moderate-to-severe ASpEF, together with 66 age- and sex-matched healthy controls. All subjects received a comprehensive evaluation at rest and 351/364 (96%) performed a combined cardiopulmonary exercise stress echocardiography test. Patients with ASpEF eligible for transcatheter aortic valve replacement (n = 125) also performed cardiac computed tomography (CT). HFpEF and ASpEF patients showed similar demographic distribution and biohumoral profiles. Most patients with ASpEF (134/150, 89%) had severe high-gradient aortic stenosis; 6/150 (4%) had normal-flow, low-gradient ASpEF, while 10/150 (7%) had low-flow, low-gradient ASpEF. Both patient groups displayed significantly lower peak oxygen consumption (VO 2 ), peak cardiac output, and peak arteriovenous oxygen difference compared to controls (all p < 0.01). ASpEF patients showed several extravalvular abnormalities at rest and during exercise, similar to HFpEF (all p < 0.01 vs. controls). Epicardial adipose tissue (EAT) thickness was significantly greater in ASpEF than HFpEF and was inversely correlated with peak VO 2 in all groups. In ASpEF, EAT was directly related to echocardiography-derived disease severity and CT-derived aortic valve calcium burden., Conclusion: Functional capacity is similarly impaired in ASpEF and HFpEF due to both peripheral and central components. Further investigation is warranted to determine whether extravalvular alterations may affect disease progression and prognosis in ASpEF even after valve intervention, which could support the concept of ASpEF as a specific sub-phenotype of HFpEF., (© 2023 European Society of Cardiology.)

Background : We evaluated the bio-humoral and non-invasive haemodynamic correlates of renal congestion evaluated by Doppler renal venous flow (RVF) across the heart failure (HF) spectrum, from asymptomatic subjects with cardiovascular risk factors (Stage A) and structural heart disease (Stage B) to patients with clinically overt HF (Stage C). Methods : Ultrasound evaluation, including echocardiography, lung ultrasound and RVF, along with blood and urine sampling, was performed in 304 patients. Results : Continuous RVF was observed in 230 patients (76%), while discontinuous RVF (dRVF) was observed in 74 (24%): 39 patients had pulsatile RVF, 18 had biphasic RVF and 17 had monophasic RVF. Stage C HF was significantly more common among patients with dRVF. Monophasic RVF was associated with worse renal function and a higher urinary albumin-to-creatinine ratio (uACR). After adjusting for hypertension, diabetes mellitus, the presence of Stage C HF and serum creatinine levels, worsening RVF patterns were associated with higher NT-proBNP levels, worse right ventricular-arterial coupling, larger inferior vena cava and higher echo-derived pulmonary artery wedge pressure. This trend was confirmed when only patients with HF Stage C were analysed after adjusting for the left ventricle ejection fraction (LVEF). Conclusion : Abnormal RVF is common across the HF spectrum. Worsening RVF patterns are independently associated with increased congestion, worse non-invasive haemodynamics and impaired RV-arterial coupling. RVF evaluation could refine prognostic stratification across the HF spectrum, irrespective of LVEF.

Aims: We investigated the prevalence and clinical value of assessing multi-organ congestion by ultrasound in heart failure (HF) outpatients., Methods and Results: Ultrasound congestion was defined as inferior vena cava of ≥21 mm, highest tertile of lung B-lines, or discontinuous renal venous flow. Associations with clinical characteristics and prognosis were explored. We enrolled 310 HF patients [median age: 77 years, median NT-proBNP: 1037 ng/L, 51% with a left ventricular ejection fraction (LVEF) <50%], and 101 patients without HF. There were no clinical signs of congestion in 224 (72%) patients with HF, of whom 95 (42%) had at least one sign of congestion by ultrasound (P < 0.0001). HF patients with ≥2 ultrasound signs were older, and had greater neurohormonal activation, lower urinary sodium concentration, and larger left atria despite similar LVEF. During a median follow-up of 13 (interquartile range: 6-15) months, 77 patients (19%) died or were hospitalized for HF. HF patients without ultrasound evidence of congestion had a similar outcome to patients without HF [reference; hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.86-1.35], while those with ≥2 ultrasound signs had the worst outcome (HR 26.7, 95% CI 12.4-63.6), even after adjusting for multiple clinical variables and NT-proBNP. Adding multi-organ assessment of congestion by ultrasound to a clinical model, including NT-proBNP, provided a net reclassification improvement of 28% (P = 0.03)., Conclusion: Simultaneous assessment of pulmonary, venous, and kidney congestion by ultrasound is feasible, fast, and identifies a high prevalence of sub-clinical congestion associated with poor outcomes., Competing Interests: Conflict of interest: P.P. has received consultancy honoraria and/or sponsorship support from Boehringer Ingelheim, Pharmacosmos, Novartis, Vifor, AstraZeneca, and Caption Health and research support from Bristol Myers Squibb. L.G. has received consultancy honoraria from GE Healthcare, Philips Healthcare, Caption Health. Other authors have no relationships relevant to the contents of this paper to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Type 2 diabetes mellitus (T2DM) represents a major health issue worldwide, as patients with T2DM show an excess risk of death for cardiovascular causes, twice as high as the general population. Among the many complications of T2DM, heart failure (HF) deserves special consideration as one of the leading causes of morbidity and reduced life expectancy. T2DM has been associated with different phenotypes of HF, including HF with reduced and preserved ejection fraction. Cardiopulmonary exercise testing (CPET) can evaluate the metabolic and ventilatory alterations related to myocardial dysfunction and/or peripheral impairment, representing a unique tool for the clinician to study the whole HF spectrum. While CPET allows for a thorough evaluation of functional capacity, it cannot directly differentiate central and peripheral determinants of effort intolerance. Combining CPET with imaging techniques could provide even higher accuracy and further insights into the progression of the disease since signs of left ventricular systolic and diastolic dysfunction can be detected during exercise, even in asymptomatic diabetic individuals. This review aims to dissect the alterations in cardiopulmonary function characterising patients with T2DM and HF to improve patient risk stratification., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Limited evidence is available regarding the role of hypertensive response to exercise (HRE) in heart failure (HF). We evaluated the systolic blood pressure (SBP) to workload slope during exercise across the HF spectrum, investigating haemodynamic and prognostic correlates of HRE., Methods and Results: We prospectively enrolled 369 patients with HF Stage C (143 had preserved [HFpEF], and 226 reduced [HFrEF] ejection fraction), 201 subjects at risk of developing HF (HF Stages A-B), and 58 healthy controls. We performed a combined cardiopulmonary exercise stress echocardiography testing. We defined HRE as the highest sex-specific SBP/workload slope tertile in each HF stage. Median SBP/workload slope was 0.53 mmHg/W (interquartile range 0.36-0.72); the slope was 39% steeper in women than men (p < 0.0001). After adjusting for age and sex, SBP/workload slope in HFrEF (0.47, 0.30-0.63) was similar to controls (0.43, 0.35-0.57) but significantly lower than Stages A-B (0.61, 0.47-0.75) and HFpEF (0.63, 0.42-0.86). Patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction. After a median follow-up of 16 months, HRE was independently associated with adverse outcomes (all-cause mortality and hospitalization for cardiovascular reasons: hazard ratio 2.05, 95% confidence interval 1.81-5.18), while rest and peak SBP were not. Kaplan-Meier analysis confirmed a worse survival probability in Stages A-B (p = 0.005) and HFpEF (p < 0.001), but not HFrEF., Conclusion: A steeper SBP/workload slope is associated with impaired functional capacity across the HF spectrum and could be a more sensitive predictor of adverse events than absolute SBP values, mainly in patients in Stages A-B and HFpEF., (© 2023 European Society of Cardiology.)

Many patients with symptoms and signs of heart failure have a left ventricular ejection fraction ≥50%, termed heart failure with preserved ejection fraction (HFpEF). HFpEF is a heterogeneous syndrome mainly affecting older people who have many other cardiac and non-cardiac conditions that often cast doubt on the origin of symptoms, such as breathlessness, or signs, such as peripheral oedema, rendering them neither sensitive nor specific to the diagnosis of HFpEF. Currently, management of HFpEF is mainly directed at controlling symptoms and treating comorbid conditions such as hypertension, atrial fibrillation, anaemia, and coronary artery disease. HFpEF is also characterized by a persistent increase in inflammatory biomarkers. Inflammation may be a key driver of the development and progression of HFpEF and many of its associated comorbidities. Detailed characterization of specific inflammatory pathways may provide insights into the pathophysiology of HFpEF and guide its future management. There is growing interest in novel therapies specifically designed to target deregulated inflammation in many therapeutic areas, including cardiovascular disease. However, large-scale clinical trials investigating the effectiveness of anti-inflammatory treatments in HFpEF are still lacking. In this manuscript, we review the role of inflammation in HFpEF and the possible implications for future trials., Competing Interests: Conflict of interest: This manuscript was handled by Guest Editor Carolyn S.P. Lam., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Ventricular-arterial coupling (VAC) can be evaluated as the ratio between arterial stiffness (pulsed wave velocity [PWV]) and myocardial deformation (global longitudinal strain [GLS])., Objectives: This study aimed to evaluate VAC across the spectrum of heart failure (HF)., Methods: The authors introduced a Doppler-derived, single-beat technique to estimate aortic arch PWV (aa-PWV) in addition to tonometry-derived carotid-femoral PWV (cf-PWV). They measured PWVs and GLS in 155 healthy controls, 75 subjects at risk of developing HF (American College of Cardiology/American Heart Association stage A-B) and 236 patients in stage C heart failure with preserved ejection fraction (HFpEF) (n = 104) or heart failure with reduced ejection fraction (HFrEF) (n = 132). They evaluated peak oxygen consumption and peripheral extraction using combined cardiopulmonary-echocardiography exercise stress., Results: aa-PWV was obtainable in all subjects and significantly lower than cf-PWV in all subgroups (P < 0.01). PWVs were directly related and increased with age (all P < 0.0001). cf-PWV/GLS was similarly compromised in HFrEF (1.09 ± 0.35) and HFpEF (1.05 ± 0.21), whereas aa-PWV/GLS was more impaired in HFpEF (0.70 ± 0.10) than HFrEF (0.61 ± 0.14; P < 0.01). Stage A-B had values of cf-PWV/GLS and aa-PWV/GLS (0.67 ± 0.27 and 0.48 ± 0.14, respectively) higher than controls (0.46 ± 0.11 and 0.39 ± 0.10, respectively) but lower than stage C (all P < 0.01). Peak arteriovenous oxygen difference (AVO 2 diff) was inversely related with cf-PWV/GLS and aa-PWV/GLS (all P < 0.01). Although cf-PWV/GLS and aa-PWV/GLS independently predicted peak VO 2 in the overall population (adjusted R 2  = 0.33 and R 2 = 0.36; all P < 0.0001), only aa-PWV/GLS was independently associated with flow reserve during exercise (R 2  = 0.52; P < 0.0001)., Conclusions: Abnormal VAC is directly correlated with greater severity of HF and worse functional capacity. HFpEF shows a worse VAC than HFrEF when expressed by aa-PWV/GLS., Competing Interests: Funding Support And Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF) is a complex clinical syndrome characterized by different etiologies and a broad spectrum of cardiac structural and functional abnormalities. Current guidelines suggest a classification based on left ventricular ejection fraction (LVEF), distinguishing HF with reduced (HFrEF) from preserved (HFpEF) LVEF. HF should also be thought of as a continuous range of conditions, from asymptomatic stages to clinically manifest syndrome. The transition from one stage to the next is associated with a worse prognosis. While the rate of HF-related hospitalization is similar in HFrEF and HFpEF once clinical manifestations occur, accurate knowledge of the steps and risk factors leading to HF progression is still lacking, especially in HFpEF. Precise hemodynamic and metabolic characterization of patients with or at risk of HF may help identify different disease trajectories and risk factors, with the potential to identify specific treatment targets that might offset the slippery slope towards overt clinical manifestations. Exercise can unravel early metabolic and hemodynamic alterations that might be silent at rest, potentially leading to improved risk stratification and more effective treatment strategies. Cardiopulmonary exercise testing (CPET) offers valuable aid to investigate functional alterations in subjects with or at risk of HF, while echocardiography can assess cardiac structure and function objectively, both at rest and during exercise (exercise stress echocardiography [ESE]). The purpose of this narrative review was to summarize the potential advantages of using an integrated CPET-ESE evaluation in the characterization of both subjects at risk of developing HF and patients with stable HF.

Aims: Pathophysiological mechanisms behind cardio-pulmonary impairment in heart failure (HF) with reduced (HFrEF) and preserved (HFpEF) ejection fraction are likely different. We analysed them using combined cardiopulmonary-exercise stress echocardiography (CPET-ESE)., Methods: We matched 1:1 subjects with HFrEF (n = 90) and HFpEF (n = 90) for age, sex, body mass index (BMI), peak oxygen consumption, and minute ventilation/carbon dioxide production slope. All patients underwent a symptom-limited graded ramp bicycle CPET-ESE compared with 40 age-, sex- and BMI-matched healthy controls., Results: During a median follow-up of 25 months, we observed 22 deaths and 80 HF hospitalisations, with similar distribution between HFpEF and HFrEF. Compared with HFrEF, HFpEF had a higher prevalence of metabolic syndrome (p = 0.02) with higher levels of high-sensitivity C-reactive protein and uric acid (p < 0.01). The multipoint mean pulmonary artery pressure/cardiac output (mPAP/CO) slope showed equally increased values in HFrEF and HFpEF (3.5 ± 1.8 and 3.7 ± 1.5 mmHg/L/min) compared with controls (1.8 ± 1.1 mmHg/L/min; p < 0.0001). During exercise, HFpEF displayed more adverse interaction of right ventricle-pulmonary artery (RV-PA; tricuspid annular plane systolic excursion/systolic pulmonary artery pressure: 0.40 ± 0.2 vs 0.47 ± 0.2 mm/mmHg in HFrEF; p < 0.01) and left atrium-left ventricle (LA-LV; LA reservoir strain/LV global longitudinal strain: 1.5 ± 0.8 vs 2.2 ± 1.1 in HFrEF; p < 0.01). The latter were independent predictors of mPAP/CO slope, along with hs-CRP (adjusted R2: 0.21; p < 0.0001)., Conclusion: Despite similar disease severity, HFpEF and HFrEF show different pathophysiological mechanisms. HFpEF is characterised by a worse LA-LV and RV-PA interaction than HFrEF, with more prevalent low-grade systemic inflammation. In HFpEF, these features may have a role in exercise-induced pulmonary hypertension., (Copyright © 2022. Published by Elsevier Inc.)

Arterial hypertension (AH) is a global burden and the leading risk factor for mortality worldwide. Haemodynamic abnormalities, longstanding neurohormonal and inflammatory activation, which are commonly observed in patients with AH, promote cardiac structural remodeling ultimately leading to heart failure (HF) if blood pressure values remain uncontrolled. While several epidemiological studies have confirmed the strong link between AH and HF, the pathophysiological processes underlying this transition remain largely unclear. The combined cardiopulmonary-echocardiography stress test (CPET-ESE) represents a precious non-invasive aid to detect alterations in patients at the earliest stages of HF. The opportunity to study the response of the cardiovascular system to exercise, and to differentiate central from peripheral cardiovascular maladaptations, makes the CPET-ESE an ideal technique to gain insights into the mechanisms involved in the transition from AH to HF, by recognizing alterations that might be silent at rest but influence the response to exercise. Identifications of these subclinical alterations might allow for a better risk stratification in hypertensive patients, facilitating the recognition of those at higher risk of evolution towards established HF. This may also lead to the development of novel preventive strategies and help tailor medical treatment. The purpose of this review is to summarise the potential advantages of using CPET-ESE in the characterisation of hypertensive patients in the cardiovascular continuum., (© 2022. The Author(s).)

Aims: Risk stratification of heart failure (HF) patients with preserved ejection fraction (HFpEF) can promote a more personalized treatment. We tested the prognostic value of a multi-parametric evaluation, including biomarkers, cardiopulmonary exercise testing-exercise stress echocardiography (CPET-ESE), and lung ultrasound, in HFpEF patients and subjects at risk of developing HF (HF Stages A and B)., Background: Risk stratification of heart failure (HF) patients with preserved ejection fraction (HFpEF) can promote a more personalized treatment., Design: We tested the prognostic value of a multi-parametric evaluation, including biomarkers, cardiopulmonary exercise testing-exercise stress echocardiography (CPET-ESE), and lung ultrasound, in HFpEF patients and subjects at risk of developing HF (HF Stages A and B)., Methods and Results: We performed a resting clinical/bio-humoural evaluation and a symptom-limited CPET-ESE in 274 patients (45 Stage A, 68 Stage B, and 161 Stage C-HFpEF) and 30 age- and sex-matched healthy controls. During a median follow-up of 18.5 months, we reported 71 HF hospitalizations and 10 cardiovascular deaths. Cox proportional-hazards regression identified five independent predictors and each was assigned a number of points proportional to its regression coefficient: stress-rest ΔB-lines >10 (3 points), peak oxygen consumption <16 mL/kg/min (2 points), minute ventilation/carbon dioxide production slope ≥36 (2 points), peak systolic pulmonary artery pressure ≥50 mmHg (1 point) and resting N-terminal pro-brain natriuretic peptide (NT-proBNP) >900 pg/mL (1 point). The event-free survival probability for low risk (<3 points), intermediate risk (3-6 points), and high risk (>6 points) were 93%, 52%, and 20%, respectively. The area under the curve (AUC) for the scoring system to predict events was 0.92 (95% CI 0.88-0.96), with an accuracy significantly higher than the individual components of the score (all P < 0.01 vs. individual AUCs)., Conclusion: A weighted risk score including NT-proBNP, markers of cardiopulmonary dysfunction and indices of exercise-induced pulmonary congestion identifies HFpEF patients at increased risk for adverse events and Stage A and B subjects more likely to progress towards more advanced HF stages., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: We evaluated the impact of echocardiographic epicardial adipose tissue (EAT) on cardiovascular haemodynamics, metabolic profile and prognosis in heart failure (HF) using combined cardiopulmonary-echocardiography exercise stress., Methods and Results: We analysed EAT thickness of HF patients with reduced (HFrEF, n = 205) and preserved (HFpEF, n = 188) ejection fraction, including 44 controls. HFpEF patients displayed the highest EAT, while HFrEF patients had lower values than controls. EAT showed an inverse correlation with natriuretic peptides, troponin T and C-reactive protein in HFrEF, while having a direct association with troponin T and C-reactive protein in HFpEF. EAT was independently associated with peak oxygen consumption (VO 2 ) and peripheral extraction (AVO 2 diff), regardless of body mass index. EAT was inversely correlated with peak VO 2 and AVO 2 diff in HFpEF, while a direct association was observed in HFrEF, where lower EAT values were associated with worse left ventricular systolic dysfunction. In HFpEF, increased EAT was related to right ventriculo-arterial (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) uncoupling. After 21 months of follow-up, 146 HF hospitalizations and 34 cardiovascular deaths were recorded in the HF population. Cox multivariable analysis supported an independent differential role of EAT in HF cohorts (interaction P = 0.01): higher risk of adverse events for increasing EAT in HFpEF [hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.04-1.37] and for decreasing EAT in HFrEF (HR 0.75, 95% CI 0.54-0.91)., Conclusion: In HFpEF, EAT accumulation is associated with worse haemodynamic and metabolic profile, also affecting survival. Conversely, lower EAT values imply higher left ventricular dysfunction, global functional impairment and adverse prognosis in HFrEF., (© 2021 European Society of Cardiology.)

Aims: Lung ultrasound B-lines are the sonographic sign of pulmonary congestion and can be used in the differential diagnosis of dyspnoea to rule in or rule out acute heart failure (AHF). Our aim was to assess the prognostic value of B-lines, integrated with echocardiography, in patients admitted to a cardiology department, independently of the initial clinical presentation, thus in patients with and without AHF, and in AHF with reduced and preserved ejection fraction (HFrEF and HFpEF)., Methods and Results: We enrolled consecutive patients admitted for various cardiac conditions. Patients were classified into three groups: (i) acute HFrEF; (ii) acute HFpEF; and (iii) non-AHF. All patients underwent an echocardiogram coupled with lung ultrasound at admission, according to standardized protocols. We followed up 1021 consecutive inpatients (69 ± 12 years) for a median of 14.4 months (interquartile range 4.6-24.3) for death and rehospitalization for AHF. During the follow-up, 126 events occurred. Admission B-lines > 30, ejection fraction < 50%, tricuspid regurgitation velocity > 2.8 m/s, and tricuspid annular plane systolic excursion < 17 mm were independent predictors at multivariable analysis. B-lines > 30 had a strong predictive value in HFpEF and non-AHF, but not in HFrEF., Conclusions: Ultrasound B-lines can detect subclinical pulmonary interstitial oedema in patients thought to be free of congestion and provide useful information not only for the diagnosis but also for the prognosis in different cardiac conditions. Their added prognostic value among standard echocardiographic parameters is more robust in patients with HFpEF compared with HFrEF., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Cardiopulmonary exercise testing (CPET) represents the gold standard to estimate peak oxygen consumption (VO 2 ) noninvasively. To improve the analysis of the mechanisms behind effort intolerance, we examined whether exercise stress echocardiography measurements relate to directly measured peak VO 2 during exercise in a large cohort of patients within the heart failure (HF) spectrum., Methods: We performed a symptom-limited graded ramp bicycle CPET exercise stress echocardiography in 30 healthy controls and 357 patients: 113 at risk of developing HF (American College of Cardiology/American Heart Association stage A-B) and 244 in HF stage C with preserved (HFpEF, n = 101) or reduced ejection fraction (HFrEF, n = 143)., Results: Peak VO 2 significantly decreased from controls (23, 21.7-29.7 mL/kg/minute; median, interquartile range) to stage A-B (18, 15.4-20.7 mL/kg/minute) and stage C (HFpEF: 13.6, 11.8-16.8 mL/kg/minute; HFrEF: 14.2, 10.7-17.5 mL/kg/minute). A regression model to predict peak VO 2 revealed that peak left ventricular (LV) systolic annulus tissue velocity (S'), peak tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (right ventricle-pulmonary artery coupling), and low-load left atrial (LA) reservoir strain/E/e' (LA compliance) were independent predictors, in addition to peak heart rate, stroke volume, and workload (adjusted R 2  = 0.76, P < .0001). The model was successfully tested in subjects with atrial fibrillation (n = 49) and with (n = 224) and without (n = 163) beta-blockers (all P < .01). Peak S' showed the highest accuracy in predicting peak VO 2  < 10 mL/kg/minute (cut point ≤ 7.5 cm/sec, area under the curve = 0.92, P < .0001) and peak VO 2  > 20 mL/kg/minute (cut point > 12.5 cm/sec, area under the curve = 0.84, P < .0001) in comparison with the other cardiac variables of the model (P < .05)., Conclusions: Peak VO 2 is directly related to measures of LV systolic function, LA compliance, and right ventricle-pulmonary artery coupling, in addition to heart rate and stroke volume and independently of workload, age, and sex. The evaluation of cardiac mechanics may provide more insights into the causes of effort intolerance in subjects from HF stages A-C., (Copyright © 2020 American Society of Echocardiography. All rights reserved.)

Aim: We combined cardiopulmonary exercise test (CPET) and exercise stress echocardiography (ESE) to identify early haemodynamic and metabolic alterations in patients with hypertension (HT) with and without heart failure with preserved ejection fraction (HFpEF)., Methods and Results: Fifty stable HFpEF-HT outpatients (mean age 68 ± 14 years) on optimal medical therapy, 63 well-controlled HT subjects (mean age 63 ± 11 years) and 32 age and sex-matched healthy controls (mean age 59 ± 15 years) underwent a symptom-limited graded ramp bicycle CPET-ESE. The acquisition protocol included left ventricular cardiac output, global longitudinal strain, E/e', peak oxygen consumption (VO 2 ), non-invasive arterial-venous oxygen content difference (AVO 2 diff) and lung ultrasound B-lines. There was a decline in peak VO 2 from controls (24.4 ± 3 mL/min/kg) to HFpEF-HT (15.2 ± 2 mL/min/kg), passing through HT (18.7 ± 2 mL/min/kg; P < 0.0001). HFpEF-HT displayed a lower peak cardiac output (9.8 ± 0.9 L/min) compared to HT (12.6 ± 1.0 L/min; P = 0.02) and controls (13.3 ± 1.0 L/min; P = 0.01). Peak AVO 2 diff was reduced in HFpEF-HT and HT (13.3 ± 2 and 13.5 ± 2 mL/dL vs. controls: 16.9 ± 2 mL/dL; P < 0.0001). A different left ventricular contractility was observed among groups, expressed as low-load global longitudinal strain (-16.8 ± 5% in HFpEF-HT, -18.2 ± 3% in HT, and 20.9 ± 3% in controls; P < 0.0001), and distribution of E/e' and B-lines [HFpEF-HT: 13.7 ± 3 and 16, interquartile range (IQR) 10-22; HT: 9.5 ± 2 and 8, IQR 4-10; controls: 6.2 ± 2 and 0, IQR 0-2; P < 0.0001]., Conclusions: Reduced peak VO 2 values in HT with and without HFpEF may be the result of decreased AVO 2 diff. CPET-ESE can also identify mild signs of left ventricular systo-diastolic dysfunction and pulmonary congestion, promoting advances in personalized therapy., (© 2020 European Society of Cardiology.)

Aims Methods and results Conclusion Uncertainty exists about defining true iron deficiency (ID) in heart failure (HF) patients. We assessed the relationship of different ID definitions with cardiac structure and function, congestion, exercise capacity, and prognosis in HF outpatients.Iron deficiency was defined according to guidelines (G‐ID: ferritin <100 ng/ml or ferritin 100–299 ng/ml with transferrin saturation [TSAT] <20%). Alternative ID definitions based on TSAT (<20%), iron (≤13 μmol/L), and ferritin (<100 or < 300 ng/ml) were explored. Relationships with rest/exercise measures of cardiac function and congestion using ultrasound, effort intolerance and adverse outcome (HF hospitalizations or all‐cause mortality) were assessed. Of 1502 patients (72% with left ventricular ejection fraction [LVEF] ≥50%), 471 (31%) had TSAT <20%, while 728 (48%) had G‐ID. Patients with TSAT <20% or G‐ID had greater left atrial volume but similar LVEF. Lower TSAT, iron and haemoglobin, but not ferritin, were associated with more signs of congestion by ultrasound. After correcting for multiple clinical variables, including haemoglobin, TSAT was directly associated with peak oxygen uptake (standardized coefficient 0.069, p = 0.041), while ferritin was not. There was no interaction with HF phenotype (HF with preserved vs. reduced LVEF). During a median follow‐up of 18 months, TSAT <20% and iron ≤13 μmol/L were associated with worse outcomes in models adjusted for clinical variables, including LVEF and N‐terminal pro‐B‐type natriuretic peptide (hazard ratio 2.48, 95% confidence interval 1.88–3.17 and 1.93, 1.48–2.52, respectively), while G‐ID or ferritin <100 or <300 ng/ml were not.In HF outpatients, TSAT <20% is more consistently associated with congestion by ultrasound and poorer functional capacity than other ID definitions, irrespective of LVEF. TSAT <20% and iron ≤13 μmol/L, but not G‐ID or ferritin‐based ID, predict a worse prognosis in HF outpatients with preserved and reduced LVEF. [ABSTRACT FROM AUTHOR]

Cardiometabolic diseases (CMDs) are interrelated and multifactorial conditions, including arterial hypertension, type 2 diabetes, heart failure, coronary artery disease, and stroke. Due to the burden of cardiovascular morbidity and mortality associated with CMDs' increasing prevalence, there is a critical need for novel diagnostic and therapeutic strategies in their management. In clinical practice, innovative methods such as epicardial adipose tissue evaluation, ventricular–arterial coupling, and exercise tolerance studies could help to elucidate the multifaceted mechanisms associated with CMDs. Similarly, epigenetic changes involving noncoding RNAs, chromatin modulation, and cellular senescence could represent both novel biomarkers and targets for CMDs. Despite the promising data available, significant challenges remain in translating basic research findings into clinical practice, highlighting the need for further investigation into the complex pathophysiology underlying CMDs. [ABSTRACT FROM AUTHOR]

Aim: Effort intolerance is frequent in patients with overweight/obesity and/or type 2 diabetes (T2D) free from cardiac and respiratory disease. We sought to quantify the independent effects of T2D and body mass index (BMI) on cardiopulmonary capacity and gain insights on the possible pathophysiology by case‐control and regression analyses. Methods: Patients at high/moderate cardiovascular risk, with or without T2D, underwent spirometry and combined echocardiography‐cardiopulmonary exercise test as part of their clinical workup. Subjects with evidence of cardiopulmonary disease were excluded. The effects of T2D and obesity were estimated by multivariable models accounting for known/potential confounders and the major pathophysiological determinants of oxygen uptake at peak exercise (VO2peak) normalized for fat‐free mass (FFM). Results: In total, 109 patients with T2D and 97 controls were included in the analysis. The two groups had similar demographic and anthropometric characteristics except for higher BMI in T2D (28.6 ± 4.6 vs. 26.3 ± 4.4 kg/m2, p =.0003) but comparable FFM. Patients with T2D achieved lower VO2peak than controls (18.5 ± 4.4 vs. 21.7 ± 8.3 ml/min/kg, p =.0006). Subclinical cardiovascular dysfunctions were observed in T2D: concentric left ventricular remodelling, autonomic dysfunction, systolic dysfunction and reduced systolic reserve. After accounting for confounders and major determinants of VO2peakFFM, T2D still displayed reduced VO2peak by 1.0 (−1.7/−0.3) ml/min/kgFFM, p =.0089, while the effect of BMI [−0.2 (−0.3/0.1) ml/min/kgFFM, p =.06 per unit increase], was largely explained by a combination of chronotropic incompetence, reduced peripheral oxygen extraction, impaired systolic reserve and ventilatory (in)efficiency. Conclusions: T2D is an independent negative determinant of VO2peak whose effect is additive to other pathophysiological determinants of oxygen uptake, including BMI. [ABSTRACT FROM AUTHOR]

Aims. We explored multiple cardiometabolic patterns, including inflammatory and congestive pathways, in patients with heart failure (HF). Methods and Results. We enrolled 270 HF patients with reduced (<50%, HFrEF; n = 96) and preserved (≥50%, HFpEF; n = 174) ejection fraction. In HFpEF, glycated hemoglobin (Hb1Ac) seemed to be relevant in its relationship with inflammation as Hb1Ac positively correlated with high-sensitivity C-reactive protein (hs-CRP; Spearman's rank correlation coefficient ρ = 0.180, p < 0.05). In HFrEF, we found a correlation between Hb1Ac and norepinephrine (ρ = 0.207, p < 0.05). In HFpEF, we found a positive correlation between Hb1Ac and congestion expressed as pulmonary B lines (ρ = 0.187, p < 0.05); the inverse correlation, although not significant, was found in HFrEF between Hb1Ac and N-terminal pro-B-type natriuretic peptide (ρ = 0.079) and between Hb1Ac and B lines (ρ = −0.051). In HFrEF, we found a positive correlation between E/e' ratio and Hb1Ac (ρ = 0.203, p < 0.05) and a negative correlation between tricuspid annular systolic excursion (TAPSE)/echocardiographically measured systolic pulmonary artery pressure (sPAP) (TAPSE/sPAP ratio) (ρ = −0.205, p < 0.05) and Hb1Ac. In HFpEF, we found a negative correlation between TAPSE/sPAP ratio and uric acid (ρ = −0.216, p < 0.05). Conclusion. In HF patients, HFpEF and HFrEF phenotypes are characterized by different cardiometabolic indices related to distinct inflammatory and congestive pathways. Patients with HFpEF showed an important relationship between inflammatory and cardiometabolic parameters. Conversely, in HFrEF, there is a significant relationship between congestion and inflammation, while cardiometabolism appears not to influence inflammation, instead affecting sympathetic hyperactivation. [ABSTRACT FROM AUTHOR]

Background: We investigated the role of the dynamic changes of pulmonary congestion, as assessed by sonographic B-lines, as a tool to stratify prognosis in patients admitted for acute heart failure with reduced and preserved ejection fraction (HFrEF, HFpEF). Methods: In this multicenter, prospective study, lung ultrasound was performed at admission and before discharge by trained investigators, blinded to clinical findings. Results: We enrolled 208 consecutive patients (mean age 76 [95% confidence interval, 70–84] years), 125 with HFrEF, 83 with HFpEF (mean ejection fraction 32% and 57%, respectively). The primary composite endpoint of cardiovascular death or HF re-hospitalization occurred in 18% of patients within 6 months. In the overall population, independent predictors of the occurrence of the primary endpoint were the number of B-lines at discharge, NT-proBNP levels, moderate-to-severe mitral regurgitation, and inferior vena cava diameter on admission. B-lines at discharge were the only independent predictor in both HFrEF and HFpEF subgroups. A cut-off of B-lines > 15 at discharge displayed the highest accuracy in predicting the primary endpoint (AUC = 0.80, p < 0.0001). Halving B-lines during hospitalization further improved event classification (continuous net reclassification improvement = 22.8%, p = 0.04). Conclusions: The presence of residual subclinical sonographic pulmonary congestion at discharge predicts 6-month clinical outcomes across the whole spectrum of acute HF patients, independent of conventional biohumoral and echocardiographic parameters. Achieving effective pulmonary decongestion during hospitalization is associated with better outcomes. [ABSTRACT FROM AUTHOR]