Algebraic Solutions for Homeostatic Mechanisms in a Minimal Closed‐Loop Cardiovascular System Model

This review focuses on the effects of altitude exposure from 1 to several days or weeks as occurs in tourists, trekkers, and mountaineers who visit high altitude and normally reside near sea level. We briefly review the acute physiological adjustments and early acclimatization that occur in the cardiovascular system and the lungs of healthy individuals. These ensure life-sustaining oxygen delivery to the tissues despite a reduction in the partial pressure of inspired oxygen between 20% and 60% at 2500 and 8000 m, respectively. One of the acute adjustments, hypoxic pulmonary vasoconstriction (HPV), may be disadvantageous in those with a vigorous response and lead to 2 potentially lethal illnesses, high-altitude pulmonary edema (HAPE) and subacute mountain sickness (SAMS), which we present in more detail. Finally, on the basis of knowledge about the acute physiological adjustments and acclimatization and, when available, a review of the literature, we discuss the high-altitude tolerance of patients with coronary artery disease, congestive heart failure, arrhythmias, systemic hypertension, and pulmonary hypertension. ### Circulation The major effects of acute hypoxia on the heart and lung are shown in Figure 1. Hypoxia directly affects the vascular tone of the pulmonary and systemic resistance vessels and increases ventilation and sympathetic activity via stimulation of the peripheral chemoreceptors.1 Interactions occur between the direct effects of hypoxia on blood vessels and the chemoreceptor-mediated responses in the systemic and pulmonary circulation. Figure 1. Effects of hypoxia on systemic and pulmonary circulation. Unraveling the underlying mechanisms of the hypoxic vasodilatation of systemic arterioles is an active area of research. Several mechanisms appear to regulate local oxygen delivery according to the needs of the tissues2,3; for instance, the release of ATP from red blood cells and the generation of NO by various ways appear to regulate local oxygen delivery according to the needs …

Congestive heart failure in the setting of a preserved left ventricular (LV) ejection fraction is increasing in prevalence among the senior population. The underlying pathophysiologic abnormalities in ventricular function and structure remain unclear for this disorder. We hypothesized that patients with heart failure with preserved ejection fraction (HFPEF) would have marked abnormalities in LV diastolic function with increased static diastolic stiffness and slowed myocardial relaxation compared with age-matched healthy controls. Eleven highly screened patients (4 men, 7 women) aged 73±7 years with HFPEF were recruited to participate in this study. Thirteen sedentary healthy controls (7 men, 6 women) aged 70±4 years also were recruited. All subjects underwent pulmonary artery catheterization with measurement of cardiac output, end-diastolic volumes, and pulmonary capillary wedge pressures at baseline; cardiac unloading (lower-body negative pressure or upright tilt); and cardiac loading (rapid saline infusion). The data were used to define the Frank-Starling and LV end-diastolic pressure-volume relationships. Doppler echocardiographic data (tissue Doppler velocities, isovolumic relaxation time, propagation velocity of early mitral inflow , E/A-wave ratio) were obtained at each level of cardiac preload. Compared with healthy controls, patients with HFPEF had similar LV contractile function and static LV compliance but reduced LV chamber distensibility with elevated filling pressures and slower myocardial relaxation as assessed by tissue Doppler imaging. In this small, highly screened patient population with hemodynamically confirmed HFPEF, increased end-diastolic static ventricular stiffness relative to age-matched controls was not a universal finding. Nevertheless, patients with HFPEF, even when well compensated, had elevated filling pressures, reduced distensibility, and increased diastolic wall stress compared with controls. In contrast, LV relaxation as assessed by tissue Doppler variables appeared consistently impaired in patients with HFPEF.

Background Left atrial (LA) compliance and contractility are key determinants of left ventricular (LV) stroke volume. LA remodelling and dysfunction in heart failure with preserved ejection fraction (HFpEF) are considered to be late presenting features, secondary to hypertension-induced LV diastolic dysfunction and chronic LA pressure overload. However, a recent unifying hypothesis has stipulated that systemic and coronary microvascular inflammation drive HFpEF pathophysiology. Considering this paradigm, we hypothesised that diminished LA compliance and contractile function occur early during HFpEF development and further impair cardiac performance. Methods Cardiac magnetic resonance imaging, echocardiography, invasive LV and LA pressure volume (PV) analysis and tissue analysis were performed in an experimental model of early-stage HFpEF (elderly dogs with renal wrap induced hypertension and exogenous aldosterone; n = 9) and young control dogs (sham surgery; n = 13). Results Early HFpEF was associated with LA enlargement, LA myocyte hypertrophy, and enhanced LA contractile function (LA active emptying fraction 18 ± 6 vs 12 ± 2%, p = 0.03; LA end-systolic PV relationship slope: 2.7 ± 0.9 HFpEF vs 1.5 ± 0.6 mmHg/mL controls, p = 0.01). However left atrioventricular systolic coupling was impaired (ratio of LV to LA end-systolic PV relationship slope 1.3 ± 0.4 HFpEF vs 0.8 ± 0.4 Controls, p 2 , p = 0.07) and inversely correlated with LA s (r=-0.66, p = 0.006). Titin isoform composition (N2BA/N2B ratio) was similar between groups, but titin hyperphosphorylation was seen in HFpEF LA and LV tissue. LA titin hyperphosphorylation correlated with LA s (r = 0.54, p = 0.03). LA microvascular reactivity was also diminished in HFpEF versus controls. Conclusions Maladaptive LA remodelling is present in early-stage experimental HFpEF and compromises overall cardiac performance. Reduced LA compliance in HFpEF may relate to contributions from LA ischaemia and titin-based cardiomyocyte stiffening. Thus, pathophysiological mechanisms involved in the development of HFpEF directly affect both atrial and ventricular myocardium.

Perioperative Transthoracic Echocardiography: “Universal Acid”?

SERCA2a Agonist Effects on Cardiac Performance During Exercise in Heart Failure With Preserved Ejection Fraction

BackgroundCardiometabolic disturbances play a central role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Due to its complexity, HFpEF is a challenging condition to treat, making phenotype-specific disease management a promising approach. However, HFpEF phenotypes are heterogenous and there is a lack of detailed evidence on the different, sex-specific profiles of cardiometabolic multimorbidity and metabolic syndrome present in HFpEF.MethodsWe performed a retrospective, modified cross-sectional study examining a subset of participants in the UK Biobank, an ongoing multi-centre prospective cohort study in the United Kingdom. We defined HFpEF as a record of a heart failure diagnosis using ICD-10 code I50, coupled with a left ventricular ejection fraction (LVEF) ≥ 50% derived from cardiac magnetic resonance (CMR) imaging. We examined sex-specific differences in cardiometabolic comorbidity burden and metabolic syndrome, performed latent class analysis (LCA) to identify distinct clusters of patients based on their cardiometabolic profile, and compared CMR imaging-derived parameters of left ventricular function at rest in the different clusters identified to reflect possible differences in adverse cardiac remodelling.ResultsWe ascertained HFpEF in 445 participants, of which 299 (67%) were men and 146 (33%) women. The median age was 70 years old (interquartile range: [66.0–74.0]). A combination of hypertension and obesity was the most prevalent cardiometabolic pattern both in men and women with HFpEF. Most men had 2–3 clinical cardiometabolic comorbidities while most women had 1–2, despite a similar metabolic syndrome profile (p = 0.05). LCA revealed three distinct, clinically relevant phenogroups, namely (1) a most male and multimorbid group (n = 117); (2) a group with a high prevalence of severe obesity, abnormal waist circumference and with the highest relative proportion of females (n = 116); and finally (3) a group with an apparently lower comorbidity burden aside from hypertension (n = 212). There were significant differences in clinical measurements and medication across the three phenogroups identified. Cardiac output at rest was significantly higher in group 2 vs. group 3 (males: median 5.6 L/min vs. 5.2 L/min, p < 0.05; females: 5.1 L/min vs. 4.4 L/min, p < 0.01). Absolute global longitudinal strain was significantly lower in women in group 1 vs. group 2 (−17.6% vs. −18.5%, p < 0.05).ConclusionWomen with cardiometabolic HFpEF had a lower comorbidity burden compared to men despite a similar metabolic syndrome profile. Based on patients’ cardiometabolic profile, we identified three distinct subgroups which differed in body shape and mass, lipid biomarker and medication profile, as well as in cardiac output at rest both in men and women. These factors may affect disease trajectory, treatment options and outcomes in those subgroups. Subject to further validation, our findings provide a refined characterisation of the cardiometabolic HFpEF phenotype, contributing towards a better understanding of the condition to enable phenotype-specific disease management.Graphical abstract

Background Exercise limitation is a key signature of heart failure with preserved ejection fraction (HFpEF) syndrome evolution with studies highlighting a significant cardiac reserve limitation and others identifying a predominant limit in the peripheral VO2 kinetics and utilization. Aims To clarify the cardiopulmonary and hemodynamic response in HFpEF according to the high or low peripheral O2 utilization patterns during maximal exercise. Materials and Method 38 patients with a HFpEF diagnosis based on the ESC HFpEFF criteria underwent cardiopulmonary exercise test (CPET) combined with stress echocardiography. Patients were divided in two groups according to the median peak c(A-V) O2 difference (Group 1: &amp;lt; 11 mL/dL and Group 2: &amp;gt; 11 mL/dL). Cardiac output (CO) was calculated by echocardiography according to the formula LVOT velocity integral x LVOT area. Data were obtained after a familiarization CPET session. Results Group 1 and 2 presented similar rest demographic, left and right hemodynamic data (table). The relationship between CO and c (A-V) O2 in terms of VO2 isopleths at peak exercise were not related to any difference in CO (figure) Conclusions In HFpEF, an impairment in O2 utilization during exercise appears independent of the cardiac reserve response (similar peak CO increase) but rather peripheral mechanisms implicated in O2 diffusion/release seem to play a dominant role, emerging as selective therapeutic targets for improving functional capacity and symptoms.

Left atrial (LA) compliance and contractility influence left ventricular stroke volume. We hypothesized that diminished LA compliance and contractile function occur early during the development of heart failure with preserved ejection fraction (HFpEF) and impair overall cardiac performance. Cardiac magnetic resonance imaging, echocardiography, left ventricular and LA pressure-volume studies, and tissue analyses were performed in a model of early HFpEF (elderly dogs, renal wrap-induced hypertension, exogenous aldosterone; n=9) and young control dogs (sham surgery; n=13). Early HFpEF was associated with LA enlargement, cardiomyocyte hypertrophy, and enhanced LA contractile function (median active emptying fraction 16% [95% confidence interval, 13-24]% versus 12 [10-14]%, P=0.008; end-systolic pressure-volume relationship slope 2.4 [1.9-3.2]mm Hg/mL HFpEF versus 1.5 [1.2-2.2]mm Hg/mL controls, P=0.01). However, atrioventricular coupling was impaired and the curvilinear LA end-reservoir pressure-volume relationship was shifted upward/leftward in HFpEF (LA stiffness constant [βLA] 0.16 [0.11-0.18]mm Hg/mL versus 0.06 [0.04-0.10]mm Hg/mL controls; P=0.002), indicating reduced LA compliance. Impaired atrioventricular coupling and lower LA compliance correlated with lower left ventricular stroke volume. Total fibrosis and titin isoform composition were similar between groups; however, titin was hyperphosphorylated in HFpEF and correlated with βLA. LA microvascular reactivity was diminished in HFpEF versus controls. LA microvascular density tended to be lower in HFpEF and inversely correlated with βLA. In early-stage hypertensive HFpEF, LA cardiomyocyte hypertrophy, titin hyperphosphorylation, and microvascular dysfunction occur in association with increased systolic and diastolic LA chamber stiffness, impaired atrioventricular coupling, and decreased left ventricular stroke volume. These data indicate that maladaptive LA remodeling occurs early during HFpEF development, supporting a concept of global myocardial remodeling.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NWO-ZonMw Background The relative impact of left ventricular (LV) diastolic dysfunction (LVDD) and impaired left atrial (LA) function on cardiac exercise performance (CEP) in heart failure with preserved ejection fraction (HFpEF) remains largely unknown Purpose To elucidate the relative effects of LVDD and impaired LA function on hemodynamics at rest and on cardiac performance during exercise by performing virtual HFpEF patient simulations. Methods Using a well-validated cardiovascular system model (CircAdapt), impaired LV relaxation was simulated by increasing the rate of myocardial relaxation (tau) from 35 to 65 ms. To study the effect of moderate and sever LV myocardial stiffness increase, LV end-diastolic elastance was increased from 0.15 mmHg/ml to 0.60 mmHg/ml and 2.00 mmHg/ml, respectively. In each simulation, LV diastolic function at rest (cardiac output (CO) and heart rate (HR) of 5.1 l/min and 70 bpm, respectively) was assessed using LV ejection fraction (LVEF), mitral E/A ratio, maximum LA volume (LAV), and mean left atrial (LA) pressure (mLAP). To investigate the relative effect of these cardiac abnormalities on exercise capacity, CO and HR were gradually increased using a fixed CO-HR relationship until mLAP exceeded a threshold pressure of 35 mmHg, which was assumed to be a physiological limit of exercise intensity. Results Simulations showed that regardless of the modelled LV and LA function, LVEF was preserved (&amp;gt;50%). Impaired LV relaxation function was associated with decreased E/A-ratio and a small increase in mLAP at rest, regardless of LA function. Increased LV passive stiffness resulted in increased E/A-ratio, LA dilation and markedly elevated mLAP at rest, regardless of LA function (Figure: top-left). Impaired LA function resulted in reduced A-peak velocity, and increased E/A–ratio, LAV and mLAP at rest regardless of LV function (Figure: top-right) Exercise simulations showed that increased LV passive stiffness exerts a stronger exercise-limiting effect than impaired LV relaxation function, in particular when LA function is impaired (Figure: bottom). Conclusions Through simple and well-controlled variations in LV and LA function, we were able to simulate virtual HFpEF patients with a wide range of LVDD severities at rest, preserved LVEF, and reduced cardiac exercise performance. In general, our simulations suggest that increased LV passive stiffness, rather than impaired LV relaxation function, reduces exercise tolerance, especially in the presence of LA dysfunction. Abstract Figure. Simulating rest &amp; exercise hemodynamics

Background The microaxial flow pump (mAFP) improve survival in selected patients with ST-elevation myocardial infarction-induced cardiogenic shock (STEMI-CS). Understanding the impact on cardiac output (CO) cardiac power output (CPO) and pulmonary artery pressure (PAP) is crucial for optimizing patient management and understanding the effect of the device. Purpose To determine the effect of mAFP on hemodynamics in STEMI-CS. Methods Substudy of the Danish-German (DanGer) shock trial, an international multicentre open-label randomized trial allocating patients with STEMI-CS to mAFP or standard of care. STEMI patients with systolic blood pressure &amp;lt;100 mmHg or ongoing use of vasopressor and lactate &amp;gt;2.5 mmol/L and left ventricular ejection fraction &amp;lt; 40% were eligible. Key exclusion criteria were comatose patients resuscitated from cardiac arrest patients with right ventricular failure and patients with mechanical infarct related complication. In addition, only patients admitted to cardiac intensive care unit (CICU) with hemodynamic monitoring using a pulmonary artery catheter were enrolled. Outcome measures were CO, CPO and mean PAP in addition native CO was estimated as CO minus estimated mAFP flow. Hemodynamic outcome measures were recorded at predefined time points during first 48 hours. Results Of 355 patients randomized 324 were admitted to CICU, 223 patients (68%) had hemodynamic monitoring, 98 (62%) in control group and 125 patients in mAFP group (74%). Patients with hemodynamic monitoring had a median age of 67 years, were predominantly males with a median systolic blood pressure on randomization of 84 mmHg, a median lactate of 4.3 mmol/L, and a median ejection fraction of 25%. Groups were well balanced. Total CO measured within 3 hours of arrival to the CICU had a median value of 3.4 L/min [IQR 2.6 – 4.4] in standard of care group compared to 3.7 L/min [3.2 – 4.5] in the mAFP group (p=0.13). After the initial 6 hours in the CICU CO increased in both groups, but increased by a greater amount in the mAFP group so that CO was significantly greater from hour 3 through hour 48 (Figure). mAFP flow upon arrival to the CICU was 3.1 L/min [2.8 – 3.3]. Native CO was 0.8 L/min [0.0 – 1.3] and remained low for the first 6 hours and increased significantly thereafter (Figure). First measured CPO within 3 hours of arrival to the CICU was 0.56 W [0.41 – 0.76] in standard of care and 0.68 W [0.51 – 0.85] in mAFP group, p=0.01 and remained higher in mAFP patients until 48 hours. The first measured mPAP within 3 hours of arrival to the CICU had a median value of 31 mmHg [29 – 39] in the standard of care group compared to 27 mmHg [23 – 33] in the mAFP group (p&amp;lt;0.001). mPAP subsequently dropped in both groups but was consistently lower in the mAFP group until 48 hours (Figure). Conclusion Use of a mAFP unloads the left ventricle by reducing native CO and PAP while maintaining CPO in STEMI-CS.

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

Seven dogs premedicated with pethidine 10 mg/kg body weight, were anaesthetized with mebumal natrium 25 mg/kg body weight i.v. and gallamoni jodidum 80 mg, together with O2‐N2O in a ratio of 1 to 1. Thereafter four dogs were constantly hyperventilated and three constantly hypoventilated under stepwise increasing anaesthesia with fluoromar® (= fluroxene), up to 6% inspiratory concentration. A change was made between the groups at this fluoromar concentration, from hyper‐ to hypoventilation and vice versa, after which the fluoromar concentration was reduced stepwise to 0% inspiratory. During the course of this anaesthesia, the related values for flow, pressure and resistance in the systemic and splanchnic circulations were measured at fluoromar concentrations: 0–1 1/2–3‐6‐6‐3‐1 1/2‐0%.The relative changes in the systemic circulation during increasing concentrations of fluoromar are independent of hypo‐ or hypercapnia, while the absolute magnitudes of the measured parameters are strongly dependent on the CO2 tensions. The hypercapnic dogs had the highest cardiac output, stroke volume and most rapid pulse, as well as the lowest peripheral resistance. The same group of dogs had the lowest liver blood flow and the greatest splanchnic resistance. The mean pressures in the aorta, right atrium and portal vein were not different between the groups.A straight line dependence at 6% fluoromar, was demonstrated between cardiac index and Paco2: cardiac index (1‐min‐1‐m‐2) = 1.22 + 0.23 ± Paco2 (kPa), ((cardiac index (1‐min‐1‐m‐2) = 1.22 + 0.03 ± Paco2 (mmHg)), and peripheral resistance and Pao2: peripheral resistance (kPa 1‐1 min) = 12.85—0.5 ± Paco2 (kPa), ((peripheral resistance (dyn‐sec‐cm‐5 ± 10‐3) = 7.72‐0.04 ± Paco2 (mmHg)). The pressure in the portal vein appears to rise and the liver flow to fall with rising carbon dioxide tension, but the relationship is not significant.In the latter half of the investigation only small changes were demonstrated which could be related to the falling concentration of fluoromar. These were slight rises in the mean pressure of the aorta and cardiac frequency, similar for both groups. In addition, a slight rise in the peripheral resistance and splanchnic resistance were observed in the hypocapnic group. No changes were seen in the cardiac output and liver flow in any of the groups during falling fluoromar concentrations. The absolute magnitude of the measured parameters in relation to the CO2 tension reflects the conditions in the first half of the investigation, but the difference between the groups is less pronounced. This was partly due to the smaller difference in Paco2 between the groups in this part of the investigation and partly due to the time and experimental course.

It has been shown that patients with cirrhosis and portal hypertension have hyperdynamic systemic and splanchnic circulation. This study was designed to assess how endoscopic variceal ligation may influence systemic and splanchnic hemodynamics. Sixteen patients with cirrhosis and esophageal varices were studied. Cardiac output and flow volume of the portal vein and the superior mesenteric artery were determined by means of duplex Doppler ultrasonography. Mean arterial pressure was also recorded. These hemodynamic measurements were performed before and after initial (3 days after initial session) and repeated (7 days after last session) variceal ligation. No significant changes in cardiac output and mean arterial pressure were found after either initial or repeated variceal ligation. Thus, systemic vascular resistance was not modified. In splanchnic hemodynamics, portal vein blood flow significantly increased after initial variceal ligation (27%, P < 0.01) but it returned to the baseline value after repeated variceal ligation. In contrast, superior mesenteric artery blood flow significantly decreased after initial variceal ligation (17%, P < 0.01) and it returned to the baseline value after repeated variceal ligation. Effect of variceal ligation on splanchnic hemodynamics is transient and variceal ligation has very little effect on systemic circulation. Thus, patients with cirrhosis underwent repeated variceal ligation still have abnormal systemic and splanchnic circulation.

Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by multiple cardiac reserve limitations during exercise. Cardiac power output (CPO) is an index of global cardiac performance and can be estimated non-invasively by echocardiography. We hypothesized that CPO reserve during exercise would be associated with impaired cardiovascular reserve, exercise intolerance, and adverse outcomes in HFpEF. Exercise stress echocardiography was performed in 425 dyspnoeic patients [217 HFpEF and 208 non-heart failure (HF) controls] to estimate CPO at rest and during exercise. We classified patients with HFpEF based on the median value of changes in CPO from rest to peak exercise (ΔCPO >0.49 W/100 g). Patients with HFpEF and a lower CPO reserve had poorer biventricular systolic function, impaired chronotropic response during exercise, and worse aerobic capacity than controls and those with a higher CPO reserve. During a median follow-up of 358 days, a composite outcome of all-cause mortality or HF events occurred in 30 patients. Patients with a lower CPO reserve had four-fold and nearly 10-fold increased risks of the outcomes compared with those with a higher CPO reserve and controls, respectively [hazard ratio (HR) 4.05, 95% confidence interval (CI) 1.16-10.1, P = 0.003 and HR 9.61, 95% CI 3.58-25.8, P < 0.0001]. We further found that a lower CPO reserve had an incremental prognostic value over the H2FPEF score and exercise duration. In contrast, resting CPO did not predict clinical outcomes in patients with HFpEF. A lower CPO reserve was associated with biventricular systolic dysfunction, chronotropic incompetence, exercise intolerance, and adverse outcomes in patients with HFpEF.

Background Atrial fibrillation (AF) is a common comorbidity in individuals with heart failure with preserved ejection fraction (HFpEF) that contributes to increased morbidity and mortality. However, the impact of AF on key HFpEF physiologic features, including exercise tolerance (peak oxygen uptake, VO2peak) hemodynamic responses, and peripheral oxygen extraction remains unclear. Purpose To compare VO2peak, peak exercise hemodynamics and arterio-venous oxygen difference (a-vO2diff) in patients with HFpEF with or without AF. Methods The study cohort included patients referred to a multi-disciplinary unexplained dyspnea clinic with an established HFpEF diagnosis after detailed clinical and hemodynamic evaluation. Patients were sub-grouped based on whether they were in AF (HFpEF-AF; n=88) or sinus rhythm (HFpEF-SR; n=625) at the time of the evaluation. Peak VO2, exercise hemodynamics and a-vO2diff were assessed from maximal cardiopulmonary exercise testing with simultaneous echocardiography (CPETecho). AF and SR sub-groups were compared using ANCOVA with adjustment for age and sex. Results The HFpEF-AF group was slightly older (76±6yrs vs 73±8yrs, P&amp;lt;0.001), with similar (P&amp;gt;0.2 for all) body mass index (28.2±4.8kg/m2 vs 29.6±11.2kg/m2), resting left-ventricular (LV) ejection fraction (61±8 vs 62±8) and LV mass index (92±36g/m2 vs 93±25g/m2) but higher indexed left-atrial volume (47±15mL/m2 vs 32±13mL/m2, P&amp;lt;0.001) and median [interquartile range] NT-proBNP levels (1200ng/L [805, 1750] vs 290ng/L [140, 530], P&amp;lt;0.001). The HFpEF-AF group also had a higher proportion of males (42% vs 55%, P=0.023), but similar prevalence of hypertension (75% vs 79%, P=0.43) and diabetes (22% vs 22%, P=0.91). Both groups showed comparable peak effort during CPETecho (peak respiratory exchange ratio: HFpEF-AF=1.06±0.11 vs HFpEF-SR=1.07±0.12, P=0.25). Peak VO2 was 9% lower in HFpEF-AF (P=0.027), accompanied by a 10% reduction in peak cardiac output (P=0.007), despite a 12% higher heart rate (P&amp;lt;0.001). Stroke volume was 19% lower in HFpEF-AF, related to smaller left ventricular end-diastolic volume (12% lower, P=0.001), which decreased further during exercise (5% decrease vs. 3% increase in HFpEF-SR, interaction P&amp;lt;0.001). In contrast, the a-vO2diff was not different between groups (P=0.94). HFpEF-AF and HFpEF-SR also showed similar resting (17.8±4.1mmHg vs 17.2±4.1 mmHg, P=0.29) and peak exercise mean pulmonary artery pressures (mPAP; 32.2±6.6mmHg vs 32.7±7.0mmHg, P=0.48), but the mPAP-CO slope tended to be 14% higher in HFpEF-AF (Fig. 1, P=0.086). Conclusions Patients with HFpEF in AF have a lower peak oxygen uptake and reduced end-diastolic volume, stroke volume and cardiac output reserve compared to patients with HFpEF in sinus rhythm. These findings highlight differences in HFpEF exercise physiology associated with AF, suggesting a potential need for tailored therapeutic approaches to optimize their functional outcomes.Fig. 1Impact of AF on exercise responsesFig. 2Impact of AF on LV responses