Punta, Lavinia Del

Abstract Background Conflicting evidence exists regarding the functional and prognostic significance of hypertensive response to exercise (HRE), commonly defined as peak systolic blood pressure (SBP) >210 mmHg in males and >190 mmHg in females. No study yet has explored the impact of sex-specific, workload-indexed HRE in patients at different stages of the heart failure (HF) spectrum, as defined by the American College of Cardiology/American Heart Association HF staging system. Purpose We evaluated the SBP/Workload slope during exercise across the HF spectrum and investigated the hemodynamic, functional and prognostic correlates of HRE. Methods Fifty-eight healthy controls, 201 subjects at risk of developing HF (HF Stages A-B), and 369 patients with a definite diagnosis of HF (Stage C) were enrolled; among the latter, 143 had preserved (HFpEF) and 226 reduced (HFrEF) left ventricular ejection fraction. All patients underwent a combined cardiopulmonary-exercise stress echocardiography test. For each patient, we recorded at least two BP measurements during exercise: the first within the first minute of exercise and the last at peak effort. The SBP/Workload slope was calculated as the difference in SBP over the corresponding increment in watts (W): (SBPpeak – SBPfirst)/(Wpeak – Wfirst). In each ACC/AHA HF Stage, we divided patients according to SBP/Workload slope tertiles; HRE was defined as the highest sex-specific SBP/Workload slope tertile. A composite of all-cause mortality and hospitalization for cardiovascular reasons was chosen as the primary outcome. Results The median SBP/Workload slope was 0.53 (interquartile range 0.36-0.72) mmHg/W and was steeper in women than in men in all subgroups (p<0.0001). After adjusting for age and sex, SBP/Workload slope was significantly higher in Stages A-B (0.61, 0.47-0.75 mmHg/W) and HFpEF (0.63, 0.42-0.86 mmHg/W) compared to controls (0.43, 0.35-0.57 mmHg/W) and HFrEF (0.47, 0.30-0.63 mmHg/W, Figure 1). In all subgroups, patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction (Table). After a median follow-up of 16 months, HRE was an independent predictor of adverse outcomes (Hazard Ratio 2.05, 95% confidence interval 1.81-5.18), while rest and peak absolute SBP values did not. Kaplan-Meier analysis confirmed a worse survival probability for patients with HRE in Stages A-B and HFpEF but not in HFrEF. After adjusting for confounding factors, the patients with the highest SBP/Workload slope had a 47% higher risk of the primary outcome than subjects in the lowest tertile (Figure 2). Conclusions Across the HF spectrum, patients with HRE, as evaluated by the SBP/Workload slope, present with peculiar pathophysiological features and impaired functional capacity. This is especially true for those in Stages A-B and patients with HFpEF. In these subgroups, HRE may portend an increased risk of adverse cardiovascular outcomes.SBP/workload slopesKaplan-Meier curves and Hazard Ratios

Objective: Limited evidence is available regarding the impact of workload-indexed hypertensive response to exercise (HRE) in patients at different stages of the heart failure (HF) spectrum. We evaluated the prevalence, pathophysiologic and prognostic correlates of HRE, evaluated by the systolic blood pressure (SBP)/Workload slope, across the HF spectrum as defined by the American College of Cardiology/American Heart Association. Design and method: We prospectively enrolled 58 healthy controls, 201 subjects at risk of developing HF (HF Stages A-B), and 369 patients with a definite diagnosis of HF (Stage C) and either preserved (HFpEF) or reduced (HFrEF) left ventricular ejection fraction. All patients underwent a combined cardiopulmonary-exercise stress echocardiography test. We recorded two SBP measurements for each patient: the first within the first minute of exercise and the last at peak effort. The SBP/Workload slope was calculated as the difference in SBP over the corresponding increment in watts (W): (SBPpeak – SBPfirst)/(Wpeak – Wfirst). In each subgroup, we divided patients according to SBP/Workload slope tertiles, using sex-specific cut-off values; HRE was defined as the highest SBP/Workload slope tertile in each HF stage. A composite of all-cause mortality and hospitalization for cardiovascular reasons was chosen as the primary outcome. Results: The median SBP/Workload slope was 0.53 (interquartile range 0.36 - 0.72) mmHg/W and was steeper in women than men in all subgroups. After adjusting for age and sex, SBP/Workload slope in controls was similar to HFrEF but significantly lower than Stages A-B and HFpEF. In all HF stages, 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 (Hazard Ratio 2.05, 95% confidence interval 1.81 - 5.18). Kaplan-Meier analysis confirmed a worse survival probability in Stages A-B and HFpEF, but not HFrEF. After adjusting for clinical and echocardiographic variables, patients in the highest SBP/Workload tertile had a 47% higher risk of the primary outcome than subjects in the lowest tertile. Conclusions: HRE is associated with peculiar pathophysiological features and possibly worse prognosis in patients in the earliest stages of cardiovascular disease and in those with HFpEF.

Abstract Funding Acknowledgements Type of funding sources: None. Background Conflicting data exist regarding the prognostic significance of hypertensive response to exercise (HRE), commonly defined according to absolute peak systolic blood pressure (SBP) values. Limited evidence is available regarding the impact of workload-indexed HRE in patients at different stages of the heart failure (HF) spectrum as defined by the American College of Cardiology/American Heart Association HF staging system. Purpose We evaluated the SBP/Workload slope during exercise across the HF spectrum and investigated the haemodynamic, functional and prognostic correlates of HRE. Methods We prospectively enrolled 58 healthy controls, 201 subjects at risk of developing HF (HF Stages A-B), and 369 patients with a definite diagnosis of HF (Stage C); among the latter, 143 had preserved (HFpEF) and 226 reduced (HFrEF) left ventricular ejection fraction. All patients underwent a combined cardiopulmonary-exercise stress echocardiography test. For each patient, we recorded the first (i.e., within the first minute of exercise) and last (i.e., at peak effort) BP measurement during the ramp protocol. The SBP/Workload slope (Figure 1) was calculated as the ratio of the difference in SBP over the corresponding increment in watts (W): (SBPpeak – SBPfirst)/(Wpeak – Wfirst). In each subgroup, we divided patients according to SBP/Workload slope tertiles; HRE was defined as the highest sex-specific SBP/Workload slope tertile in each HF stage. The primary outcome was a composite of all-cause mortality and hospitalization for cardiovascular reasons. Results Median SBP/Workload slope was 0.53 mmHg/W, interquartile range 0.36-0.72 mmHg/W; the slope was 39% steeper in women than in men (p<0.0001). After adjusting for age and sex, SBP/Workload slope in controls (0.43, 0.35-0.57 mmHg/W) was similar to HFrEF (0.47, 0.30-0.63 mmHg/W) but significantly lower than Stages A-B (0.61, 0.47-0.75 mmHg/W) and HFpEF (0.63, 0.42-0.86 mmHg/W). In all HF stages, 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 (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. After adjusting for age, sex, body mass index, rest and peak SBP, rest and peak cardiac output, and rest and peak left ventricular ejection fraction, patients with the highest SBP/Workload slope had a 47% higher risk of the primary outcome than subjects in the lowest tertile (Figure 2). Conclusion HRE, as evaluated by the SBP/Workload slope, is associated with distinct pathophysiological features and impaired functional capacity across the HF spectrum, especially in Stages A-B and in patients with HFpEF. Patients with HRE in these subgroups may be at increased risk of adverse cardiovascular outcomes.

Abstract 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.

Abstract Funding Acknowledgements Type of funding sources: None. Background. Recent evidence shows epicardial adipose tissue (EAT) acts as a paracrine organ and may directly alter myocardial function by exerting mechanical compression. Purpose. We evaluated EAT thickness through transthoracic echocardiography and investigated its relationship with cardiopulmonary fitness and cardiovascular haemodynamics at rest and during exercise in a population of heart failure (HF) patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction. Methods. We prospectively enrolled 393 consecutive HF outpatients (205 HFrEF, 188 HFpEF) who had been referred to our hospital due to dyspnoea and/or effort intolerance, together with 44 healthy controls. We performed a resting state-of-the-art echocardiographic evaluation, followed by combined cardiopulmonary-echocardiography exercise stress. Results. EAT thickness was higher in HFpEF (median 8 mm, interquartile range [IQR] 4–12 mm) and progressively reduced in controls (median 5 mm, IQR 3–7 mm; p < 0.0001) and HFrEF (median 3 mm, IQR 2–6 mm). In HFpEF, EAT thickness was inversely correlated with peak oxygen consumption (VO2) and peripheral oxygen extraction (AVO2diff), while a direct association was observed for the same parameters in HFrEF (Figure 1). Furthermore, EAT independently predicted peak VO2 and AVO2diff in HFrEF and HFpEF regardless of body mass index and waist circumference. These relationships were direct in HFrEF (standard regression coefficient [SRC] for peak VO2: 0.18, p = 0.02; SRC for peak AVO2diff: 0.17, p = 0.03) and indirect in HFpEF (SRC for peak VO2: -0.33, p < 0.0001; SRC for peak AVO2diff: -0.25, p < 0.0001). As there are no definite cut-off values to define increased EAT, patients were divided based on the median EAT value (5 mm) of the overall population. Thinner EAT (≤5 mm) was associated with worse LV systolic dysfunction (peak average S’) and remodeling (3D LV mass index) in HFrEF. In HFpEF, on the other hand, increased EAT (>5 mm) was related to worse right ventricular systolic dysfunction (3D right ventricular ejection fraction) and more severe left atrio-ventricular (left atrium reservoir strain/left ventricle global longitudinal strain) and right ventriculo-arterial (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) coupling (Figure 2). Conclusion. In HFpEF, increased EAT thickness is associated with a worse hemodynamic profile and functional capacity. Conversely, in HFrEF, EAT thinning portends more advanced LV dysfunction and impaired cardiopulmonary fitness. Abstract Figure 1 Abstract Figure 2

Abstract Funding Acknowledgements Type of funding sources: None. Background. Recent evidence shows that increased epicardial adipose tissue (EAT) thickness is associated with metabolic syndrome, microvascular dysfunction and enhanced pericardial restraint. Purpose. We measured echocardiography-derived EAT thickness in a population of heart failure (HF) patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction to examine the relationship between EAT and prognosis at clinical follow-up. Methods. We prospectively enrolled 393 consecutive HF outpatients (205 HFrEF, 188 HFpEF) who had been referred to our hospital due to dyspnoea and/or effort intolerance. We performed a resting clinical and biohumoral evaluation, followed by combined cardiopulmonary-echocardiography exercise stress. We considered a composite endpoint of cardiovascular death and HF-related hospitalization during follow-up. Results. Patients with HFpEF displayed greater EAT thickness (median 8 mm, interquartile range [IQR] 4–12 mm) than HFrEF (median 3 mm, IQR 2–6 mm; p < 0.0001). During a median follow-up of 20.9 months (IQR 15-25 months), 34 cardiovascular deaths and 146 HF hospitalizations were reported, with no significant differences between the two HF phenotypes. EAT was shown to predict adverse events independently from body mass index, waist circumference and other well-established prognostic markers in HF (such as NT-proBNP and peak oxygen consumption). The risk of adverse events increased with increasing EAT thickness in HFpEF and with EAT thinning in HFrEF. Kaplan-Meier analyses for the composite endpoint showed that in HFpEF, the survival probability was significantly lower in patients with thicker EAT than those with thinner EAT. In HFrEF, conversely, patients with increased EAT thickness had a higher survival probability than those with reduced EAT thickness (Figure 1). Conclusion. EAT accumulation is increased in HFpEF compared to HFrEF and carries different prognostic meanings in the two subsets. In HFpEF, EAT thickening portends adverse outcomes, which may be due to the secretion of pro-inflammatory and pro-atherogenic adipokines and increased mechanical restraint. In HFrEF, EAT thinning is associated with a worse prognosis, probably reflecting a more advanced catabolic state (e.g., cardiac cachexia). Larger studies are needed to determine whether or not EAT has a causal role in influencing progression and survival in the different HF phenotypes. Abstract Figure 1

Abstract Background Increased epicardial adipose tissue (EAT) thickness correlates with metabolic syndrome, insulin resistance, microvascular dysfunction and enhanced pericardial restraint. Purpose We measured echocardiographic EAT thickness in heart failure (HF) patients with reduced (HFrEF) or preserved (HFpEF) ejection fraction to determine whether EAT could bear prognostic significance at clinical follow-up. Methods We prospectively enrolled 393 consecutive HF outpatients (205 HFrEF, 188 HFpEF) referred to our hospital due to dyspnoea and/or effort intolerance. We performed a resting clinical and biohumoral evaluation, followed by combined cardiopulmonary-echocardiography exercise stress. A composite of cardiovascular death and HF-related hospitalization was chosen as endpoint during follow-up. Results Patients with HFpEF displayed higher EAT thickness (median 8 mm, interquartile range [IQR] 4–12 mm) than HFrEF (median 3 mm, IQR 2–6 mm; p<0.0001). During a median follow-up of 20.9 months (IQR 15–25 months), we reported 34 cardiovascular deaths and 146 HF hospitalizations, with no significant differences between the two HF subsets. EAT predicted adverse events independently from body mass index and well-established markers of poor prognosis (e.g., NT-proBNP, peak oxygen consumption). The risk of adverse events increased with increasing EAT thickness in HFpEF and with EAT thinning in HFrEF. Kaplan-Meier analyses for the composite endpoint showed that in HFpEF, the survival probability was significantly lower in patients with thicker EAT than those with thinner EAT. In HFrEF, conversely, patients with thicker EAT had a higher survival probability than those with reduced EAT thickness (Figure 1). Conclusion EAT accumulation is more marked in HFpEF than HFrEF and carries different prognostic meanings in the two subsets. In HFpEF, EAT thickening portends adverse outcome, which may be due to increased mechanical restraint and secretion of pro-inflammatory and pro-atherogenic adipokines. In HFrEF, greater EAT thickness seems to have a protective role, while EAT thinning is associated with a worse prognosis, likely reflecting a catabolic state (i.e. cardiac cachexia). Larger studies will clarify whether EAT is a bystander or an active player in the different HF phenotypes. Funding Acknowledgement Type of funding sources: None. Figure 1

Abstract Background Epicardial adipose tissue (EAT) acts as a paracrine organ and could exert direct mechanical compression on the myocardium. Purpose We investigated the impact of echocardiographic EAT thickness on metabolic profile and cardiovascular hemodynamics at rest and during exercise in heart failure (HF) patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction Methods We prospectively enrolled 393 consecutive HF outpatients (205 HFrEF, 188 HFpEF) referred to the our hospital due to dyspnoea and/or effort intolerance. We performed a resting clinical and biohumoral evaluation, followed by combined cardiopulmonary-echocardiography exercise stress. The protocol also included 44 healthy controls. Results Patients with HFpEF displayed the greatest EAT thickness (median 8 mm, interquartile range [IQR] 4–12 mm), while those with HFrEF had thinner EAT (median 3 mm, IQR 2–6 mm) than controls (median 5 mm, IQR 3–7 mm; p<0.0001). In HFrEF, EAT thickness was inversely associated with natriuretic peptides, Troponin T, and C-reactive protein levels. In HFpEF, it was directly correlated with Troponin-T and C-reactive protein levels. EAT thickness was inversely correlated with peak oxygen consumption (VO2) and peripheral oxygen extraction (AVO2diff) in HFpEF, while a direct association was observed in HFrEF (Fig 1). EAT resulted in an independent predictor of peak VO2 and AVO2diff in HFrEF and HFpEF regardless of body mass index, but the relationships were direct in HFrEF (standard regression coefficient [SRC] for peak VO2: 0.18, p=0.02; SRC for peak AVO2diff: 0.17, p=0.03) and indirect in HFpEF (SRC for peak VO2: −0.33, p<0.0001; SRC for peak AVO2diff: −0.25, p<0.0001). The analysis of cardiac mechanics revealed that thinner EAT was associated with worse left ventricle systolic dysfunction (average S') and remodeling (3D left ventricle mass) in HFrEF. In HFpEF, increased EAT was related to more severe left atrio-ventricular (left atrium reservoir strain/left ventricle global longitudinal strain) and right ventriculo-arterial (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) coupling (Figure 2). Conclusion In HFpEF, EAT accumulation is associated with worse hemodynamic and metabolic profile. In HFrEF, conversely, EAT thinning portends more severe LV dysfunction and impaired global functional capacity. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Abstract 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.