Hyperlactataemia is a marker of reduced exercise capacity in heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is associated with an array of central and peripheral haemodynamic and metabolic changes. The exact pathogenesis of exercise limitation in HFpEF remains uncertain. Our aim was to compare lactate accumulation and central haemodynamic responses to exercise in patients with HFpEF, non-cardiac dyspnoea (NCD), and healthy volunteers. METHODS AND RESULTS: Right heart catheterization with mixed venous blood gas and lactate measurements was performed at rest and during symptom-limited supine exercise. Multivariable analyses were conducted to determine the relationship between haemodynamic and biochemical parameters and their association with exercise capacity. Of 362 subjects, 198 (55%) had HFpEF, 103 (28%) had NCD, and 61 (17%) were healthy volunteers. This included 139 (70%) females with HFpEF, 77 (75%) in NCD (P = 0.41 HFpEF vs. NCD), and 31 (51%) in healthy volunteers (P < 0.001 HFpEF vs. volunteers). The median age was 71 (65, 75) years in HFpEF, 66 (57, 72) years in NCD, and 49 (38, 65) years in healthy volunteers (HFpEF vs. NCD or volunteer, both P < 0.001). Peak workload was lower in HFpEF compared with healthy volunteers [52 W (interquartile range 31-73), 150 W (125-175), P < 0.001], but not NCD [53 W (33, 75), P = 0.85]. Exercise lactate indexed to workload was higher in HFpEF at 0.08 mmol/L/W (0.05-0.11), 0.06 mmol/L/W (0.05-0.08; P = 0.016) in NCD, and 0.04 mmol/L/W (0.03-0.05; P < 0.001) in volunteers. Exercise cardiac index was 4.5 L/min/m2 (3.7-5.5) in HFpEF, 5.2 L/min/m2 (4.3-6.2; P < 0.001) in NCD, and 9.1 L/min/m2 (8.0-9.9; P < 0.001) in volunteers. Oxygen delivery in HFpEF was lower at 1553 mL/min (1175-1986) vs. 1758 mL/min (1361-2282; P = 0.024) in NCD and 3117 mL/min (2667-3502; P < 0.001) in the volunteer group during exercise. Predictors of higher exercise lactate levels in HFpEF following adjustment included female sex and chronic kidney disease (both P < 0.001). CONCLUSIONS: HFpEF is associated with reduced exercise capacity secondary to both central and peripheral factors that alter oxygen utilization. This results in hyperlactataemia. In HFpEF, plasma lactate responses to exercise may be a marker of haemodynamic and cardiometabolic derangements and represent an important target for future potential therapies.

Cardiac Substrate Utilization and Relationship to Invasive Exercise Hemodynamic Parameters in HFpEF.

The authors conducted transcardiac blood sampling in healthy subjects and subjects with heart failure with preserved ejection fraction (HFpEF) to compare cardiac metabolite and lipid substrate use. We demonstrate that fatty acids are less used by HFpEF hearts and that lipid extraction is influenced by hemodynamic factors including pulmonary pressures and cardiac index. The release of many products of protein catabolism is apparent in HFpEF compared to healthy myocardium. In subgroup analyses, differences in energy substrate use between female and male hearts were identified.

Predictors of pacemaker requirement in patients receiving implantable loop recorders for unexplained syncope: A systematic review and meta-analysis.

BACKGROUND: Implantable loop recorders (ILRs) are increasingly used to evaluate patients with unexplained syncope. Identification of all predictors of bradycardic syncope and consequent permanent pacemaker (PPM) insertion is of substantial clinical interest as patients in the highest risk category may benefit from upfront pacemaker insertion. OBJECTIVE: We performed a systematic review and meta-analysis to identify risk predictors for PPM insertion in ILR recipients with unexplained syncope. METHODS: An electronic database search (MEDLINE, Embase, Scopus, Cochrane) was performed in June 2023. Studies evaluating ILR recipients with unexplained syncope and recording risk factors for eventual PPM insertion were included. A random effects model was used to calculate the pooled odds ratio (OR) for clinical and electrocardiographic characteristics with respect to future PPM requirement. RESULTS: Eight studies evaluating 1007 ILR recipients were included; 268 patients (26.6%) underwent PPM insertion during study follow-up. PPM recipients were older (mean age, 70.2 ± 15.4 years vs 61.6 ± 19.7 years; P < .001). PR prolongation on baseline electrocardiography was a significant predictor of PPM requirement (pooled OR, 2.91; 95% confidence interval, 1.63-5.20). The presence of distal conduction system disease, encompassing any bundle branch or fascicular block, yielded a pooled OR of 2.88 for PPM insertion (95% confidence interval, 1.53-5.41). Injurious syncope and lack of syncopal prodrome were not significant predictors of PPM insertion. Sinus node dysfunction accounted for 62% of PPM insertions, whereas atrioventricular block accounted for 26%. CONCLUSION: Approximately one-quarter of ILR recipients for unexplained syncope require eventual PPM insertion. Advancing age, PR prolongation, and distal conduction disease are the strongest predictors for PPM requirement.

The Impact of Diabetes on Haemodynamic and Cardiometabolic Responses in Heart Failure With Preserved Ejection Fraction.

AIMS: Heart failure with preserved ejection (HFpEF) and diabetes mellitus (DM) commonly co-exist. However, it is unclear if DM modifies the haemodynamic and cardiometabolic phenotype in patients with HFpEF. We aimed to interrogate the haemodynamic and cardiometabolic effects of DM in HFpEF. METHODS: We compared the haemodynamic and metabolic profiles of non-DM patients and patients with DM-HFpEF at rest and during exercise using right heart catheterisation and mixed venous blood gas analysis. RESULTS: Of 181 patients with HFpEF, 37 (20%) had DM. Patients with DM displayed a more adverse exercise haemodynamic response vs HFpEF alone (mean pulmonary arterial pressure: 47 mmHg [interquartile range {IQR} 42-55] vs 42 [38-47], p<0.001; workload indexed pulmonary capillary wedge pressure indexed: 0.80 mmHg/W [0.44-1.23] vs 0.57 [0.43-1.01], p=0.047). HFpEF-DM patients had a lower mixed venous oxygen saturation at rest (70% [IQR 66-73] vs 72 [69-75], p=0.003) and were unable to enhance O2 extraction to the same extent (Δ-28% [-33 to -15] vs -29 [-36 to -21], p=0.029), this occurred at a 22% lower median workload. Resting mixed venous lactate levels were higher in those with DM (1.5 mmol/L [IQR 1.1-1.9] vs 1 [0.9-1.3], p<0.001), and during exercise indexed to workload (0.09 mmol/L/W [0.06-0.13] vs 0.08 [0.05-0.11], p=0.018). CONCLUSION: Concurrent diabetes and HFpEF was associated with greater metabolic responses at rest, with enhanced wedge driven pulmonary hypertension and relative lactataemia during exercise without appropriate augmentation of oxygen consumption.

Caudal fluoroscopic guidance for the insertion of transvenous pacing leads.

BACKGROUND: Pneumothorax is a well-recognized complication of cardiac implantable electronic device (CIED) insertion. While AP fluoroscopy alone is the most commonly imaging technique for subclavian or axillary access, caudal fluoroscopy (angle 40°) is routinely used at our institution. The caudal view provides additional separation of the first rib and clavicle and may reduce the risk of pneumothorax. We assessed outcomes at our institution of AP and caudal fluoroscopic guided pacing lead insertion. METHODS: Retrospective cohort study of consecutive patients undergoing transvenous lead insertion for pacemakers, defibrillators, and cardiac resynchronization therapy devices between 2011 and 2023. Both de novo and lead replacement/upgrade procedures were included. Data were extracted from operative, radiology, and discharge reports. All patients underwent postprocedure chest radiography. RESULTS: Three thousand two hundred fifty-two patients underwent insertion of pacing leads between February 2011 and March 2023. Mean age was 71.1 years (range 16-102) and 66.7% were male. Most (n = 2536; 78.0%) procedures used caudal guidance to obtain venous access, while 716 (22.0%) procedures used AP guidance alone. Pneumothoraxes occurred in five (0.2%) patients in the caudal group and five (0.7%) patients in the AP group (p = .03). Subclavian contrast venography was performed less frequently in the caudal group (26.2% vs. 42.7%, p < .01). CONCLUSION: Caudal fluoroscopy for axillary/subclavian access is associated with a lower rate of pneumothorax and contrast venography compared with an AP approach.

The challenge of risk stratification in hypertrophic cardiomyopathy: Clinical, genetic and imaging insights from a quaternary referral centre.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the commonest genetic cardiomyopathy and may result in sudden cardiac death (SCD). Clinical risk stratification scores are utilised to estimate SCD risk and determine potential utility of a primary prevention implantable cardioverter defibrillator (ICD). METHODS: Patients with a confirmed diagnosis of HCM from a quaternary HCM service were defined according to clinical characteristics, genetic profiles and cardiac imaging results. European Risk-SCD score and American Heart Association / American College of Cardiology (AHA/ACC) Score were calculated. The primary outcome was cardiac arrest. RESULTS: 380 patients with HCM were followed up for a median of 6.4 years. 18 patients (4.7%) experienced cardiac arrest, with predictive factors being younger age (37.2 vs 54.4 years, p = 0.0041), unexplained syncope (33.3% vs 9.4%, p = 0.007), non-sustained ventricular tachycardia (50.0% vs 12.7%, p < 0.0001), increased septal thickness (21.5 vs 17.5 mm, p = 0.0003), and presence of a sarcomeric gene mutation (100.0% vs 65.8%, p = 0.038). The Risk-SCD and AHA/ACC scores had poor agreement (kappa coefficient 0.38). Risk-SCD score had poor sensitivity (44.4%), classifying 55.6% of patients with cardiac arrest as low-risk but was highly specific (93.7%). AHA/ACC risk score did not discriminate between groups significantly. 20 patients (5.3%) died, with most >60-year-olds having a non-cardiac cause of death (p = 0.0223). CONCLUSION: This study highlights limited (38%) agreement between the Risk-SCD and AHA/ACC scores. Most cardiac arrests occurred in ostensibly low or medium-risk patients under both scores. Appropriate ICD selection remains challenging. Incorporating newer risk markers such as HCM genotyping and myocardial fibrosis quantification by cardiac MRI may assist future risk refinement.

Transvenous versus subcutaneous implantable cardioverter defibrillators in young cardiac arrest survivors.

Secondary prevention implantable cardioverter defibrillators (ICDs) are indicated in young patients presenting with aborted sudden cardiac death (SCD) because of ventricular arrhythmias. Transvenous-ICDs (TV-ICDs) are effective, established therapies supported by evidence. The significant morbidity associated with transvenous leads led to the development of the newer subcutaneous-ICD (S-ICD). This review discusses the clinical considerations when selecting an ICD for the young patient presenting with out-of-hospital cardiac arrest. The major benefits of TV-ICDs are their ability to pace (antitachycardia pacing [ATP], bradycardia support and cardiac resynchronisation therapy [CRT]) and the robust evidence base supporting their use. Other benefits include a longer battery life. Significant complications associated with transvenous leads include pneumothorax and tamponade during insertion and infection and lead failure in the long term. Comparatively, S-ICDs, by virtue of having no intravascular leads, prevent these complications. S-ICDs have been associated with a higher incidence of inappropriate shocks. Patients with an indication for bradycardia pacing, CRT or ATP (documented ventricular tachycardia) are seen as unsuitable for a S-ICD. If venous access is unsuitable or undesirable, S-ICDs should be considered given the patient is appropriately screened. There is a need for further randomised controlled trials to directly compare the two devices. TV-ICDs are an effective therapy for preventing SCD limited by significant lead-related complications. S-ICDs are an important development hindered largely by an inability to pace. Young patients stand to gain the most from a S-ICD as the cumulative risk of lead-related complications is high. A clinical framework to aid decision-making is presented.

Subcutaneous defibrillator use with unipolar pacemakers: Cautiously possible.

Implantation of subcutaneous implantable cardioverter-defibrillator in a patient with existing unipolar pacemaker is against manufacturer recommendations. We report the case of a successful subcutaneous implantable cardioverter-defibrillator implantation in a patient with Fontan circulation and concomitant active unipolar pacing and present a summary of recommendations when considering subcutaneous implantable cardioverter-defibrillator implantation with unipolar pacing. Recommendations included: pre-procedure screening, rescreening during implantation and ventricular fibrillation induction, pacemaker programming, and post-procedure investigations.

Atrial Fibrillation Ablation for Heart Failure With Preserved Ejection Fraction: A Randomized Controlled Trial.

BACKGROUND: Patients with heart failure with preserved ejection fraction (HFpEF) frequently develop atrial fibrillation (AF). There are no randomized trials examining the effects of AF ablation on HFpEF outcomes. OBJECTIVES: The aim of this study is to compare the effects of AF ablation vs usual medical therapy on markers of HFpEF severity, including exercise hemodynamics, natriuretic peptide levels, and patient symptoms. METHODS: Patients with concomitant AF and HFpEF underwent exercise right heart catheterization and cardiopulmonary exercise testing. HFpEF was confirmed with pulmonary capillary wedge pressure (PCWP) of 15 mm Hg at rest or ≥25 mm Hg on exercise. Patients were randomized to AF ablation vs medical therapy, with investigations repeated at 6 months. The primary outcome was change in peak exercise PCWP on follow-up. RESULTS: A total of 31 patients (mean age: 66.1 years; 51.6% females, 80.6% persistent AF) were randomized to AF ablation (n = 16) vs medical therapy (n = 15). Baseline characteristics were comparable across both groups. At 6 months, ablation reduced the primary outcome of peak PCWP from baseline (30.4 ± 4.2 to 25.4 ± 4.5 mm Hg; P < 0.01). Improvements were also seen in peak relative VO2 (20.2 ± 5.9 to 23.1 ± 7.2 mL/kg/min; P < 0.01), N-terminal pro-B-type natriuretic peptide levels (794 ± 698 to 141 ± 60 ng/L; P = 0.04), and MLHF (Minnesota Living with Heart Failure) score (51 ± -21.9 to 16.6 ± 17.5; P < 0.01). No differences were detected in the medical arm. Following ablation, 50% no longer met exercise right heart catheterization-based criteria for HFpEF vs 7% in the medical arm (P = 0.02). CONCLUSIONS: AF ablation improves invasive exercise hemodynamic parameters, exercise capacity, and quality of life in patients with concomitant AF and HFpEF.

Diagnostic evaluation of unexplained ventricular tachyarrhythmias in younger adults.

BACKGROUND: The diagnostic work-up for cardiac arrest from ventricular tachyarrhythmias occurring in younger adults and structurally normal hearts is variable and often incomplete. METHODS: We reviewed records for all recipients of a secondary prevention implantable cardiac defibrillator (ICD) younger than 60 years at a single quaternary referral hospital from 2010 to 2021. Patients with unexplained ventricular arrhythmias (UVA) were identified as those with no structural heart disease on echocardiogram, no obstructive coronary disease, and no clear diagnostic features on ECG. We specifically evaluated the adoption rate of five modalities of "second-line" cardiac investigations: cardiac magnetic resonance imaging (CMR), exercise ECG, flecainide challenge, electrophysiology study (EPS), and genetic testing. We also evaluated patterns of antiarrhythmic drug therapy and device-detected arrhythmias and compared them with secondary prevention ICD recipients with a clear etiology found on initial assessment. RESULTS: One hundred and two recipients of a secondary prevention ICD under the age of 60 were analyzed. Thirty-nine patients (38.2%) were identified with UVA and were compared with the remaining 63 patients with VA of clear etiology (61.8%). UVA patients were younger (35.6 ± 13.0 vs. 46.0 ± 8.6 years, p < .001) and were more often female (48.7% vs. 28.6%, p = .04). CMR was performed in 32 patients with UVA (82.1%), whereas flecainide challenge, stress ECG, genetic testing, and EPS were only performed in a minority of patients. Overall, the use of a second-line investigation suggested an etiology in 17 patients with UVA (43.5%). Compared to patients with VA of clear etiology, UVA patients had lower rates of antiarrhythmic drug prescription (64.1% vs. 88.9%, p = .003) and had a higher rate of device-delivered tachy-therapies (30.8% vs. 14.3%, p = .045). CONCLUSION: In this real-world analysis of patients with UVA, the diagnostic work-up is often incomplete. While CMR was increasingly utilized at our institution, investigations for channelopathies and genetic causes appear to be underutilized. Implementation of a systematic protocol for work-up of these patients requires further study.

Impact of device length on electrogram sensing in miniaturized insertable cardiac monitors.

BACKGROUND: Little data exists on electrogram sensing in current generation of miniaturized insertable cardiac monitors (ICMs). OBJECTIVE: To compare the sensing capability of ICM with different vector length: Medtronic Reveal LINQ (~40 mm) vs. Biotronik Biomonitor III (BM-III, ~70 mm). METHODS: De-identified remote monitoring transmissions from n = 40 patients with BM-III were compared with n = 80 gender and body mass index (BMI)-matched patients with Reveal LINQ. Digital measurement of P- and R-wave amplitude from calibrated ICM electrograms was undertaken by 3 investigators independently. Further, we evaluated the impact of BMI and gender on P-wave visibility. RESULTS: Patients in both groups were well matched for gender and BMI (53% male, mean BMI 26.7 kg/m2, both p = NS). Median P- and R-wave amplitude were 97% & 56% larger in the BM-III vs. LINQ [0.065 (IQR 0.039-0.10) vs. 0.033 (IQR 0.022-0.050) mV, p < .0001; & 0.78 (IQR 0.52-1.10) vs. 0.50 (IQR 0.41-0.89) mV, p = .012 respectively). The P/R-wave ratio was 36% greater with the BM-III (p < .001). The 25th percentile of P-wave amplitude for all 120 patients was .026 mV. Logistic regression analysis showed BM-III was more likely than LINQ to have P-wave amplitude ≥.026 mV (OR 7.47, 95%CI 1.965-29.42, p = .003), and increasing BMI was negatively associated with P-wave amplitude ≥.026 mV (OR 0.84, 95%CI 0.75-0.95, p = .004). However, gender was not significantly associated with P-wave amplitude ≥.026 mV (p = .37). CONCLUSION: The longer ICM sensing vector of BM-III yielded larger overall P- and R- wave amplitude than LINQ. Both longer sensing vector and lower BMI were independently associated with greater P-wave visibility.

Prediction of Pacemaker Requirement in Patients With Unexplained Syncope: The DROP Score.

BACKGROUND: Implantable loop recorders (ILR) are increasingly utilised in the evaluation of unexplained syncope. However, they are expensive and do not protect against future syncope. OBJECTIVES: To compare patients requiring permanent pacemaker (PPM) implantation during ILR follow-up with those without abnormalities detected on ILR in order to identify potential predictors of benefit from upfront pacing. METHODS: We analysed 100 consecutive patients receiving ILR: Group 1 (n=50) underwent PPM insertion due to bradyarrhythmias detected on ILR; Group 2 (n=50) had no arrhythmias detected on ILR over >3 years follow-up. Baseline clinical characteristics, syncope history, electrocardiographic and echocardiographic parameters were assessed to identify predictors of ultimate requirement for pacing. RESULTS: Group 1 (64% male, median age 70.8 years; IQR 65.5-78.8) were older than Group 2 (58% male, median 60.2 years; IQR 44.0-73.0 p=0.001) and were less likely to have related historical factors such as overheating, posture and exercise (98% vs 70% p<0.001). PR interval was also longer in Group 1 (192±51 vs 169±23 p=0.006) with greater prevalence of distal conduction system disease (30% vs 4.3% p=0.002). Significant univariate predictors for PPM insertion were distal conduction disease (p=0.007), first degree atrioventricular (AV) block (p=0.003), absence of precipitating factors (p=0.004), and age >65 years (p=0.001). Injury sustained, recurrent syncope, history of atrial fibrillation (AF) or heart failure, left atrial (LA) size and left ventricular ejection fraction (LVEF) were not predictive. These significant predictors were incorporated into the DROP score1 (0-4). Using time-to-event analysis, no patients with a score of 0 progressed to pacing, while higher scores (3-4) strongly predicted pacing requirement (log-rank p<0.001). CONCLUSION: The DROP score may be helpful in identifying patients likely to benefit from upfront permanent pacemaker (PPM) insertion following unexplained syncope. Larger prospective studies are required to validate this tool.

Characterization of Cardiac Sympathetic Nervous System and Inflammatory Activation in HFpEF Patients.

We have shown that systemic and cardiac sympathetic activation is present in heart failure with preserved ejection fraction (HFpEF) patients. Conversely, whereas systemic inflammatory activation was also detected in HFpEF, we did not detect local myocardial release of inflammatory cytokines. Activation of the sympathetic system correlated with both hemodynamic and demographic factors that characteristically cluster together in HFpEF. Together these data suggest that there may be a role for antiadrenergic therapies in certain HFpEF patients. The study does not implicate locally derived cytokines in the myocardial biology of HFpEF, although systemic sources may contribute to the global pathophysiology of HFpEF.

Long-Term Implications of Pacemaker Insertion in Younger Adults: A Single Centre Experience.

BACKGROUND: The long-term implications of pacemaker insertion in younger adults are poorly described in the literature. METHODS: We performed a retrospective analysis of consecutive younger adult patients (18-50 yrs) undergoing pacemaker implantation at a quaternary hospital between 1986-2020. Defibrillators and cardiac resynchronisation therapy devices were excluded. All clinical records, pacemaker checks and echocardiograms were reviewed. RESULTS: Eighty-one (81) patients (median age 41.0 yrs IQR=35-47.0, 53% male) underwent pacemaker implantation. Indications were complete heart block (41%), sinus node dysfunction (33%), high grade AV block (11%) and tachycardia-bradycardia syndrome (7%). During a median 7.9 (IQR=1.1-14.9) years follow-up, nine patients (11%) developed 13 late device-related complications (generator or lead malfunction requiring reoperation [n=11], device infection [n=1] and pocket revision [n=1]). Five (5) of these patients were <40 years old at time of pacemaker insertion. At long-term follow-up, a further nine patients (11%) experienced pacemaker-related morbidity from inadequate lead performance managed with device reprogramming. Sustained ventricular tachycardia was detected in two patients (2%). Deterioration in ventricular function (LVEF decline >10%) was observed in 14 patients (17%) and seven of these patients required subsequent biventricular upgrade. Furthermore, four patients (5%) developed new tricuspid regurgitation (>moderate-severe). Of 69 patients with available long-term pacing data, minimal pacemaker utilisation (pacing <5% at all checks) was observed in 13 (19%) patients. CONCLUSIONS: Pacemaker insertion in younger adults has significant long-term implications. Clinicians should carefully consider pacemaker insertion in this cohort given risk of device-related complications, potential for device under-utilisation and issues related to lead longevity. In addition, patients require close follow-up for development of structural abnormalities and arrhythmias.

Prescription trends and costs of diabetes medications in Australia between 2003 and 2019: an analysis and review of the literature.

BACKGROUND: Since the turn of the century, the prevalence of diabetes mellitus in Australia has increased, primarily due to rising rates of Type 2 diabetes. Simultaneously, the landscape of diabetes medications has evolved significantly. The change in prescribing trends and public spending on diabetes medications within Australia during this period are not well defined. AIMS: To establish the frequency and cost of dispensed diabetes medications in the Australian public healthcare system between 2003 and 2019. METHODS: We performed a longitudinal nationwide observational study using data obtained from the Pharmaceutical Benefits Scheme (PBS) and Medicare Benefits Schedule websites, which contain information on frequency and spending of diabetes medications dispensed in Australia. RESULTS: The total number of PBS-subsidised prescriptions dispensed for diabetes increased from 5 218 690 in 2003 to 12 188 568 in 2019, and spending increased from $117 241 031 to $598 904 983. Of the non-insulin agents, metformin was consistently the most frequently dispensed agent, with a rapid growth in metformin combination tablets. Dispensation of sulphonylureas and thiazolidinediones have declined, with a simultaneous increase in dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists. CONCLUSIONS: Our data show a large growth in the use of diabetes medications between 2003 and 2019. The rapid growth in dispensing of drugs with proven cardiovascular and renal benefits reflect the evolving approach of diabetes treatment, from a historical approach targeting glycaemic control alone, to a modern individualised approach targeting specific co-morbidities.

Comprehensive Physiological Modeling Provides Novel Insights Into Heart Failure With Preserved Ejection Fraction Physiology.

Background Although a rapid rise in left atrial pressure during exertion is considered pathognomonic of heart failure with preserved ejection fraction (HFpEF), the fundamental circulatory determinants of this response are not clear, impacting upon the development of more effective therapies. We aimed to comprehensively describe the circulatory mechanics of patients with HFpEF at rest and during exercise in comparison with controls. Methods and Results We performed simultaneous right-heart catheterization and echocardiography at rest and during exercise in 22 healthy control volunteers and 60 patients with confirmed HFpEF. Using detailed individual patient-level hemodynamic and left ventricular ejection fraction data we performed computer simulations to evaluate the circulatory parameters including the estimated stressed blood volumethat contribute to the resting and exercise pulmonary capillary pressure. At rest and during exercise, left ventricular stiffness (V30, the end-diastolic pressure-volume relationship at a filling pressure of 30 mm Hg), left ventricular elastance, and arterial elastance were all significantly greater in HFpEF than in controls. Stressed blood volume was significantly greater in HFpEF (26.9±5.4 versus 20.2±4.7 mL/kg, P<0.001), becoming even more pronounced during exercise (40.9±3.7 versus 27.5±7.0 mL per 70 kg, P<0.001). During exercise, the magnitude of the change in stressed blood volume (r=0.67, P<0.001) and left ventricular stiffness (r=-0.44, P<0.001) were key determinants of the rise in pulmonary capillary wedge pressure. Further detailed modeling studies showed that the hemodynamic response to exercise results from a complex non-linear interaction between circulatory parameters. Conclusions The circulatory determinants of HFpEF physiology are complex. We identified stressed blood volume at rest and during exercise is a novel, key factor, therebyrepresenting an important potential therapeutic target.