Patients with heart failure with preserved ejection fraction represent half of the heart failure patients nowadays, an at least steady trend due to the aging of the population. We investigated whether the parameters obtained from cardiopulmonary exercise testing (CPET) correlated with the prognosis of these patients. This prospective observational cohort study assesses the relationship between the CPET parameters peakVO2 and VE/VCO2 slope and the number of heart failure hospitalizations or cardiovascular death of these patients.

From August 2016 until May 2019, 99 patients from our outpatient unit with newly diagnosed heart failure with preserved ejection fraction underwent CPET. Median follow-up was 30 months [interquartile range, 24-38.5]. We selected peakVO2 < 14 mL/min/kg and a VE/VCO2 slope > 34 as threshold values for our primary clinically relevant endpoint, a composite of hospitalization for heart failure or cardiovascular death. Mean age was 75.07 ± 7.31 years, 49% were women, 75% were at NYHA class II and median NTproBNP was 511 pg/mL. Mean peakVO2 was 15.09 ± 4.75, and mean VE/VCO2 was 36.05 ± 6.60. During follow-up, there were 207 all-cause hospitalizations, 126 cardiovascular hospitalizations, 58 heart failure hospitalizations and 4 deaths. Over a median follow-up of 30 months, the primary clinically relevant endpoint occurred in 5 of 40 patients (12.5%) with a VE/VCO2 slope ≤ 34 and in 19 of 59 patients (32.2%) with a VE/VCO2 slope > 34 [hazard ratio, 2.69; 95% confidence interval (CI), 1.00-7.21; P = 0.04]. On multivariate analysis, VE/VCO2 slope was independently associated with heart failure hospitalization or cardiovascular death as a terminal event.

In patients with heart failure with preserved ejection fraction, a VE/VCO2 slope > 34 predicts heart failure hospitalizations and cardiovascular death.

Obesity, insulin resistance (IR), and diabetes are common in heart failure with preserved ejection fraction (HFpEF) and are associated with worsening heart failure, but their independent contributions remain unknown.

In this study, we sought to determine the contribution of diabetes vs obesity to left heart abnormalities in HFpEF METHODS: Indices of adiposity (body mass index [BMI], bioimpedance fat mass, waist circumference) and IR (homeostasis-model assessment [HOMA]) were measured among PVDOMICS study participants with HFpEF. Rest and exercise pulmonary capillary wedge pressure (PCWP) responses were compared, stratified by obesity (BMI ≥30 kg/m2), IR status (HOMA-IR ≥2.6), and diabetes diagnosis. Findings were also tested in an independent HFpEF cohort.

Of 276 patients with HFpEF, 246 (89%) had increased waist/height ratio, and 166 (60%) had BMI ≥30 kg/m2, with 114 (69%) of the latter having IR and 75 (45%) having diabetes. Of 110 (40%) with HFpEF and BMI <30 kg/m2, 44 (40%) had IR and 27 (25%) had diabetes (both P < 0.0001 vs obesity phenotype). The presence of IR was not associated with worse left heart remodeling or PCWP. In contrast, obesity (regardless of IR status) was associated with greater biventricular enlargement, worse exercise performance, poorer quality of life, and higher rest and exercise PCWP (P < 0.01 for all). Obesity was associated with higher rest and dynamic PCWP responses (+4.4 mm Hg; 95% CI: +2.5 to +6.4 mm Hg; P < 0.0001), even after adjustment for HOMA-IR (+4.7 mm Hg; 95% CI: +2.7 to +6.7 mm Hg; P < 0.0001). Greater fat mass, BMI, and waist circumference were associated with higher PCWP at rest and exercise (P < 0.0009 for all), but HOMA-IR was not (+0.01 mm Hg; 95% CI: -0.13 to +0.16 mm Hg; P = 0.84). Findings were similar evaluating diabetes in place of IR, and were replicated in the independent HFpEF cohort (n = 254), where BMI remained independently associated with higher rest and exercise PCWP (+0.19 mm Hg [95% CI: +0.11 to +0.27 mm Hg] per kg/m2; P < 0.0001), but diabetes was not.

Excess adiposity is present in most patients with HFpEF, even among those not considered obese according to BMI, calling for further study of cardiometabolic therapies among patients with HFpEF and excess adiposity with BMI <30 kg/m2. Although excess body fat is associated with IR and diabetes, cardiac remodeling, hemodynamics, and functional impairment are independently correlated with body fat, but not IR. These findings suggest that diabetes is primarily a marker of greater adiposity in HFpEF, with less direct impact on heart failure severity. (Pulmonary Vascular Disease Phenomics Program [PVDOMICS]; NCT02980887).

Unexplained exertional dyspnoea without significant elevation of natriuretic peptides is common. One of the causes might be early heart failure with preserved ejection fraction (HFpEF).

This study aimed to characterize patients with exertional dyspnoea and normal/near-to-normal N-terminal pro-brain natriuretic peptide (NT-proBNP) levels with regard to early stages of HFpEF and non-cardiac causes.

Sixty-six patients (age 62 ± 7 years old, 85% women) with dyspnoea assessed using the Multidimensional Dyspnea Profile (MDP) questionnaire and NT-proBNP level of <125 pg/mL for patients <75 years old or <300 pg/mL for patients >75 years old were recruited. Patients with known significant heart disease, lung disease (abnormal respiratory function tests) or renal insufficiency stage ≥ 4 were excluded. In 11 patients (16.7%), HFpEF was confirmed according to the European Society of Cardiology Heart Failure Association (ESC HFA) criteria, 31 patients (47%) presented isolated deconditioning and 5 patients (7.6%) had idiopathic hyperventilation. In the remaining 19 patients (28.8%) with normal echocardiography and cardiopulmonary exercise testing (CPX), no objective cause of dyspnoea could be found. Compared with patients without HFpEF, those with HFpEF were older, more often hypertensive and diabetic, with higher NT-proBNP levels. They had higher E/e' ratios during exercise echocardiography and lower volume of oxygen uptake (VO2) peaks and steeper minute ventilation (VE)/volume of carbon dioxide produced (VCO2) slopes during CPX. Psychological impact measured on the Short Form-36 (SF-36) questionnaire was less important in HFpEF patients than in other patients.

The most common causes of unexplained exertional dyspnoea in patients without significant elevation of natriuretic peptides are peripheral deconditioning, HFpEF and hyperventilation. Studying patients during exercise allows for getting more data about pathophysiology and improving patient phenotyping and management. Early unmasking of HFpEF using exercise echocardiography and/or CPX and initiation of treatment could prevent hospitalizations for acute heart failure. Although using exercise testing, many patients could not be classified according to their diagnosis, and this reinforces the need to better define exercise diagnostic criteria.

The American Heart Association (AHA) guidelines assess heart failure (HF) via comorbidities, laboratory markers, and echocardiography, while the New York Heart Association (NYHA) classification evaluates functional capacity. The primary objective of this study was to investigate the correlation between objectified HF-related symptoms and cardiac and muscular exercise capacity in Stage B HF patients with non-reduced ejection fraction. As secondary endpoints, we stratified this analysis for subgroups of NYHA classes to evaluate the primary endpoint for different levels of impairment and for sex to address for differences between men and women. Sixty-two Stage B HF patients with non-reduced EF were screened from an HF-risk cohort. Assessments included medical history, HF-related symptoms (Kansas City Cardiomyopathy Questionnaire, KCCQ), physical examination, laboratory tests, echocardiography, and cardiopulmonary exercise testing (CPET) with cardiac output monitoring. Correlations were analyzed between KCCQ score and exercise capacity markers: maximal oxygen uptake (VO2max), arterio-venous oxygen difference (avDO2), cardiac power output (CPO), mean arterial pressure (MAP), and respiratory efficiency (Ve/VO2). Subgroup analyses were performed by sex and NYHA class determined by VO2max or KCCQ functional scores. Our HF patient cohort showed reduced KCCQ scores (78.3) and VO₂max (22.9 ml/kg/min), and a progressed reduction in avDO₂. In the total cohort, KCCQ scores showed moderate correlations with Ve/VO₂ (r = -0.39) and MAP (r = 0.27). NYHA stratification by VO₂max revealed differences in avDO₂ and cardiac output but not KCCQ scores, while KCCQ-functional stratification only showed differences in Ve/VO₂. Sex-specific analysis showed KCCQ scores correlated with CPO in men (r = 0.65) and Ve/VO2 in women (r = -0.68). Our identified Stage B HFpEF cohort showed already alterations in total, cardiac and muscular exercise limitation. The HF symptom severity was weakly associated to the higher blood pressure and ventilatory inefficiency and, but moderately to strongly correlated CPO in men and Ve/VO2 in women in sex-specific analyses.

Heart failure with preserved ejection fraction (HFpEF) poses a significant challenge in contemporary medicine, characterized by poor quality of life, high healthcare costs, and increased mortality. Despite advancements in medical research, treatment strategies for HFpEF remain elusive, with unclear guidance on the use of beta-blockers. While sympathetic overstimulation is common in HFpEF, beta-blockers, though potentially beneficial in reducing sympathetic activity, may exacerbate chronotropic incompetence and decrease exercise tolerance. Additionally, their impact on outcomes in HFpEF patients with concurrent atrial fibrillation is uncertain. Some studies suggest the potential benefits of beta-blockers on diastolic function, yet evidence on clinical endpoints remains inconclusive. Recent research indicates a potential reduction in all-cause mortality with beta-blocker use in HFpEF, although their effect on combined mortality or HF hospitalizations is less clear. Moreover, beta-blocker efficacy may vary depending on ejection fraction subgroups, with more favorable outcomes observed in HFmrEF compared to HFpEF. Current literature underscores the need for large-scale randomized clinical trials to clarify the role of beta-blockers in HFpEF management. Given the limitations of existing evidence, future research is essential to inform updated treatment guidelines and therapeutic protocols tailored to the contemporary clinical landscape.

Patients with Fontan palliation have reduced aerobic capacity because of impaired cardiac, pulmonary, and skeletal muscle function. However, the assessment of aerobic capacity in this population still relies on comparisons with people without cardiovascular disease rather than comparison with the expected aerobic capacity of other Fontan patients. The purpose of this study was to determine the expected aerobic capacity of adults with Fontan palliation.

Adults with Fontan palliation who underwent a cardiopulmonary exercise test at Mayo Clinic (2003-2023) were stratified into quartiles based on the predicted peak oxygen consumption (VO2). We assessed the correlates of predicted peak VO2 and the relationship between predicted peak VO2 quartiles and cardiovascular outcomes (death/transplant).

Of 323 patients (age, 29±9 years; 177 [55%] men), the median peak VO2 was 19.1 (15.2-23.9) mL/kg per minute, and this corresponds to a predicted peak VO2 of 51% (range, 19-88; interquartile range, 41-62). After multivariable adjustments, the correlates of predicted peak VO2 were body mass index (β±SE, -2.61±0.95; 2.61% decrease in predicted peak VO2 per 5 kg/m2 increase in body mass index; P=0.009), systemic saturation (β±SE, 3.65±0.85; 3.65% increase in predicted peak VO2 per 5% increase in oxygen saturation; P<0.001), and Fontan pressure (β±SE, -1.24±0.22; 1.24% decrease in predicted peak VO2 per 1 mm Hg increase in Fontan pressures; P<0.001). There was a 47% increase in the risk for death/transplant from a higher predicted peak VO2 quartile to the next lower quartile (adjusted hazard ratio, 1.47 [95% CI, 1.09-2.05]; P=0.01).

The results of the current study would help calibrate the interpretation of exercise test data in adults with Fontan palliation and improve risk stratification in this population. It also underscores the need to maintain normal Fontan hemodynamics and body weight, which are important determinants of aerobic capacity.

Heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD) have a strong pathophysiological interrelationship, and their combination worsens prognosis.

This article briefly reviews the bidirectional epidemiological burden and the pathophysiological interplay between HFpEF and CKD. It also discusses some of the controversial aspects regarding the diagnosis and screening of HFpEF in CKD patients and focuses on the most effective therapeutic approaches to improve symptoms and prognosis in this high-risk population.

Due to its prevalence and prognostic significance, HFpEF screening should be considered in patients with CKD, with careful use of traditional diagnostic tools in this population. Optimal medical therapy has seen major recent advances in patients with both HFpEF and CKD. SGLT2 inhibitors, finerenone, and semaglutide have consistently demonstrated cardio- and renoprotective effects in both conditions.

Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We developed a novel "two-hit" model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57Bl6/NJ mice fed a high-fat diet (HFD) for > 10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d. HFD-Renin (aka "HFpEF") mice demonstrated obesity and insulin resistance, moderate left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by echocardiographic measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to human HFpEF. Treatment with empagliflozin, an effective but incompletely understood HFpEF therapy, improved multiple endpoints. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Additional preclinical HFpEF models allow for orthogonal studies to increase validity in assessment of interventions.

The left atrial assist device (LAAD) is a novel continuous-flow pump designed to treat patients with heart failure with preserved ejection fraction, a growing type of heart failure, but with limited device-treatment options. The LAAD is implanted in the mitral plane and pumps blood from the left atrium into the left ventricle. The purpose of this study was to refine the initial design of the LAAD, using results from computational fluid dynamics (CFD) analyses to inform changes that could improve hydraulic performance and flow patterns within the LAAD.

The initial design and three variations were simulated, exploring changes to the primary impeller blades, the housing shape, and the number, size, and curvature of the diffuser vanes. Several pump rotational speeds and flow rates spanning the intended range of use were modeled.

Guided by the insight gained from each design iteration, the final design incorporated impeller blades with improved alignment relative to the incoming flow and wider, more curved diffuser vanes that better aligned with the approaching flow from the volute. These design adjustments reduced flow separation within the impeller and diffuser regions. In vitro testing confirmed the CFD predicted improvement in the hydraulic performance of the revised LAAD flow path design.

The CFD results from this study provided insight into the key pump design-related parameters that can be adjusted to improve the LAAD's hydraulic performance and internal flow patterns. This work also provided a foundation for future studies assessing the LAAD's biocompatibility under clinical conditions.

The pericardium plays an important role in modulating cardiac performance and hemodynamics in patients with heart failure with preserved ejection fraction (HFpEF). Pericardial constraint increases filling pressures in patients with HFpEF, particularly those with the obesity phenotype, atrial myopathy, right ventricular dysfunction, and tricuspid regurgitation. Preclinical and early stage clinical studies indicate that pericardiotomy may become a novel treatment for HFpEF. This review summarizes and discusses the pathophysiology of pericardial restraint and the possibility of pericardiotomy in HFpEF.

Pathologic abnormalities in skeletal muscle and the systemic vasculature are common in patients with systemic sclerosis (SSc). These abnormalities may lead to impaired systemic peripheral oxygen extraction (EO 2 ), known as neurovascular dysregulation, which may be because of abnormal blood flow distribution in the vasculature, microvascular shunting, and/or skeletal muscle mitochondrial dysfunction. Findings from invasive cardiopulmonary exercising testing (iCPET) provide important insights and enable diagnosis and treatment of this SSc disease manifestation.

Recent findings from noninvasive cardiopulmonary exercise testing (niCPET) support the existence of neurovascular dysregulation in patients with SSc. Invasive cardiopulmonary exercise testing (iCPET) has pointed to reduced systemic vascular distensibility as a possible mechanism for neurovascular dysregulation in patients with connective tissue diseases, including SSc.

Neurovascular dysregulation is likely an underappreciated cause of exercise impairment and dyspnea in patients with SSc in the presence or absence of underlying cardiopulmonary disease. It is posited to be related to microcirculatory and muscle dysfunction. Further studies are needed to clarify the pathophysiology of neurovascular dysregulation in SSc and to identify novel treatment targets and additional therapies.

Cardiopulmonary exercise testing (CPET) combined with exercise echocardiography (CPETecho) allows simultaneous assessments of cardiac, pulmonary, and ventilation in heart failure (HF) with preserved ejection fraction (HFpEF). This study sought to determine whether simultaneous assessment of CPET variables could provide additive predictive value over exercise stress echocardiography in patients with dyspnoea.

CPETecho was performed in 443 patients with suspected HFpEF (240 HFpEF and 203 controls without HF). Patients with HFpEF were divided based on peak oxygen consumption (VO2, ≥10 or <10 ml/min/kg) or the slope of minute ventilation to carbon dioxide production (VE vs. VCO2 slope ≥45.0 or <45.0). The primary endpoint was defined as a composite of all-cause mortality, HF hospitalization, unplanned hospital visits requiring intravenous diuretics, or intensification of oral diuretics. During a median follow-up of 399 days, the composite outcome occurred in 57 patients. E/e' ratio during peak exercise was associated with adverse outcomes. Patients with HFpEF and lower peak VO2 had increased risks of the composite event (hazard ratio [HR] 5.05, 95% confidence interval [CI] 2.65-9.62, p < 0.0001 vs. controls; HR 3.14, 95% CI 1.69-5.84, p = 0.0003 vs. HFpEF with higher peak VO2). Elevated VE versus VCO2 slope was also associated with adverse events in HFpEF. The addition of either the presence of abnormal peak VO2 or VE versus VCO2 slope increased the predictive ability over the model based on age, sex, atrial fibrillation, left atrial volume index, and exercise E/e' (p < 0.05).

These data provide new insights into the role of CPETecho in patients with HFpEF.

Although cardiopulmonary exercise testing (CPET) parameters have known prognostic value in adults after Fontan palliation, there are limited data correlating treadmill CPET with invasive exercise hemodynamics. Furthermore, the invasive hemodynamic underpinnings of exercise limitations have not been thoroughly investigated. This is a retrospective analysis of 55 adults (age ≥18 years) with prior Fontan palliation who underwent treadmill CPET before invasive exercise hemodynamic testing using a supine cycle protocol between November 2018 and April 2023. The median age was 32.2 (IQR 24.1; 37.2) years. The peak heart rate (HR) was 139.7 ± 28.1 beats per minute and the peak oxygen consumption (VO2) was 19.1 ± 5.7 ml/kg/min (47.4 ± 13.5% predicted). VO2/HR was directly related to exercise stroke volume index (r = 0.50, p = 0.0002), whereas no association was seen with exercise arterio-mixed venous O2 content difference (r = 0.14, p = 0.32). Peak HR was inversely related to exercise pulmonary artery (PA) pressures (r = -0.61, p <0.0001) and PA wedge pressures (PAWP) (r = -0.61, p <0.0001). Moreover, %predicted VO2 was inversely related to exercise PA pressures (r = -0.50, p <0.0001) and PAWP (r = -0.55, p <0.0001). Peak VO2 ≤19.1 ml/kg/min had a sensitivity of 81% and a specificity of 76% (area under the curve 0.82) for predicting a ΔPAWP/ΔQs ratio >2 mmHg/L/min and/or a ΔPA/ΔQp >3 mmHg/L/min, whereas a predicted peak VO2 ≤48% had a sensitivity of 74% and a specificity of 81% (area under the curve 0.79) for the same parameters. In summary, lower peak HR and peak VO2 were associated with higher exercise PAWP and PA pressure. Peak VO2 ≤48% predicted provided the optimal cutoff for predicting increased indexed exercise PAWP or PA pressures; therefore, low peak VO2 should alert clinicians of abnormal underlying hemodynamics.

Cardiac amyloidosis, encompassing both transthyretin (ATTR) and light-chain (AL) types, poses considerable challenges in patient management due to its intricate pathophysiology and progressive course. This narrative review elucidates the pivotal role of cardiopulmonary exercise testing (CPET) in the assessment of these patients. CPET is essential for evaluating disease progression by measuring cardio-respiratory performance and providing prognostic insights. This functional test is crucial not only for tracking the disease trajectory, but also for assessing the effectiveness of disease-modifying therapies. Moreover, CPET facilitates the customization of therapeutic strategies based on individual patient performance, enhancing personalized care. By objectively measuring parameters such as peak oxygen uptake (VO2 peak), ventilatory efficiency, and exercise capacity, clinicians can gain a deeper understanding of the degree of functional impairment and make informed decisions regarding treatment initiation, adjustment, and anticipated outcomes. This review emphasizes the importance of CPET in advancing personalized medicine approaches, ultimately striving to improve the quality of life and clinical outcomes for patients with cardiac amyloidosis.

Despite remarkable progress in therapeutic drugs, morbidity, and mortality for heart failure (HF) remains high in developed countries. HF with preserved ejection fraction (HFpEF) now accounts for around half of all HF cases. It is a heterogeneous disease, with multiple aetiologies, and as such poses a significant diagnostic challenge. Cardiac magnetic resonance (CMR) has become a valuable non-invasive modality to assess cardiac morphology and function, but beyond that, the multi-parametric nature of CMR allows novel approaches to characterize haemodynamics and with magnetic resonance spectroscopy (MRS), the study of metabolism. Furthermore, exercise CMR, when combined with lung water imaging provides an in-depth understanding of the underlying pathophysiological and mechanistic processes in HFpEF. Thus, CMR provides a comprehensive phenotyping tool for HFpEF, which points towards a targeted and personalized therapy with improved diagnostics and prevention.

Increases in pulmonary capillary wedge pressure (PCWP) during exercise reduce pulmonary artery (PA) compliance, increase pulsatile right ventricular (RV) afterload, and impair RV-PA coupling in patients with heart failure with preserved ejection fraction (HFpEF). The effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on pulmonary vascular properties and RV-PA coupling are unknown.

To test the effect of dapagliflozin on right ventricular performance and pulmonary vascular load during exertion in HFpEF.

Evaluation of the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction (CAMEO-DAPA) randomized clinical trial demonstrated improvement in PCWP at rest and exercise over 24 weeks with dapagliflozin compared with placebo with participants recruited between February 2021 and May 2022. This secondary analysis evaluates the effects of dapagliflozin on pulsatile pulmonary vascular load and RV-PA coupling using simultaneous echocardiography and high-fidelity invasive hemodynamic testing with exercise. This was a single-center study including patients with hemodynamically confirmed HFpEF with exercise PCWP of 25 mm Hg or greater.

Dapagliflozin or placebo for 24 weeks.

Pulsatile pulmonary vascular load (PA compliance and elastance) and right ventricular performance (PA pulsatility index, RV systolic velocity [s']/PA mean) during rest and exercise.

Among 37 randomized participants (mean [SD] age, 67.4 [8.5] years; 25 female [65%]; mean [SD] body mass index, 34.9 [6.7]; calculated as weight in kilograms divided by height in meters squared), there was no effect of dapagliflozin on PA loading or RV-PA interaction at rest. However, with exercise, dapagliflozin improved PA compliance (placebo-corrected mean difference, 0.57 mL/mm Hg; 95% CI, 0.11-1.03 mL/mm Hg; P = .02) and decreased PA elastance (stiffness; -0.17 mm Hg/mL; 95% CI, -0.28 to -0.07 mm Hg/mL; P = .001). RV function during exercise improved, with increase in PA pulsatility index (0.33; 95% CI, 0.08-0.59; P = .01) and increase in exercise RV s' indexed to PA pressure (0.09 cm·s-1/mm Hg; 95% CI, 0.02-0.16 cm·s-1/mm Hg; P = .01). Improvements in pulsatile RV load and RV-PA coupling were correlated with reduction in right atrial (RA) pressure (PA elastance Pearson r = 0.55; P =.008; RV s'/PA elastance Pearson r = -0.60; P =.002) and PCWP (PA elastance Pearson r = 0.58; P <.001; RV s'/PA elastance Pearson r = -0.47; P = .02). Dapagliflozin increased resistance-compliance time (dapagliflozin, median [IQR] change, 0.06 [0.03-0.15] seconds; placebo, median [IQR] change, 0.01 [-0.02 to 0.05] seconds; P =.046), resulting in higher PA compliance for any exercise pulmonary vascular resistance.

Results of this randomized clinical trial reveal that treatment with dapagliflozin for 24 weeks reduced pulsatile pulmonary vascular load and enhanced dynamic RV-PA interaction during exercise in patients with HFpEF, findings that are related to the magnitude of PCWP reduction. Benefits on dynamic right ventricular-pulmonary vascular coupling may partially explain the benefits of SGLT2 inhibitors in HFpEF.

ClinicalTrials.gov Identifier: NCT04730947.

Despite half of all heart failure patients suffering from heart failure with preserved ejection fraction (HFpEF), treatment options are limited. This study aims to compare safety and efficacy of standard pacemaker programming (DDD or DDDR) and a novel pacing algorithm PressurePace™ (BaroPace Inc, Issaquah, WA, USA) which modulates atrial pacing rate based on blood pressure (BPAP).

This prospective, randomized, double-blind, non-significant risk proof of concept study was conducted at two large cardiology clinics in Los Angeles, California, USA. Subjects underwent two modified Bruce protocol graded treadmill exercise tests in which pacemaker programming was randomized to either standard programming (DDD or DDDR), or BPAP at least 1 week apart. Physiological measurements of heart rate (HR), and systolic and diastolic blood pressure (BP) were collected at 2 min intervals. During the BPAP treadmill test, the pacemaker activity sensor was disabled. The PressurePace algorithm instructed the pacemaker technician to modify or leave unchanged the atrial pacing rate based on these BP measurements. Subjects and clinical staff were blinded to pacemaker programming, only the pacemaker technician was unblinded.

Ten subjects with HFpEF associated with hypertension who also had permanent dual-chamber pacemakers, previously implanted for standard clinical indications, participated in the study. Mean age was 70.1 ± 6.8 years, left ventricular ejection fraction of 54.8 ± 1.9%. Exercise duration increased in all 10 subjects, when paced in the BPAP mode compared with standard pacemaker programming, showing a mean increase of 117 s (26%, P = 0.0016). The algorithm could adjust HR at each 2 min interval. The majority of subjects (60%) had their atrial pacing rate increased an average of 20% at t = 2 min. In the remaining 40% of subjects, the algorithm instructed HR to be unchanged. In two subjects, the pacing rate was not increased until t = 6 min. In contrast, subjects programmed to DDDR experienced an average of 45% increase in atrial pacing rate at t = 2 min. In the post-treadmill recovery period, SBP was higher for subjects who underwent BPAP. This difference in SBP was most pronounced immediately post-treadmill and diminished as subjects progressed through the 30 min recovery period. Statistical significance was achieved at t = 0, 20, and 30 min post-treadmill.

An increase in exercise duration was reported in HFpEF subjects using a pacing algorithm that modulated HR based on BP compared with standard programming. These encouraging results form the basis for a larger, randomized cross-over trial to confirm these initial observations, further characterize the safety, efficacy, and possible mechanisms of action in both acute and longer-term treatment.

A considerable proportion of candidates for transcatheter aortic valve implantation (TAVI) have underlying heart failure (HF) with preserved ejection fraction (HFpEF), which can be challenging for diagnosis because significant valvular heart disease should be excluded before diagnosing HFpEF. This study investigated the long-term prognostic value of the pre-procedural H2FPEF score in patients with preserved ejection fraction (EF) undergoing TAVI.

Patients who underwent TAVI between October 2013 and May 2017 were enrolled from the Optimized CathEter vAlvular iNtervention-Transcatheter Aortic Valve Implantation Japanese multicentre registry. After excluding 914 patients, 1674 patients with preserved EF ≥ 50% (median age: 85 years, 72% female) were selected for calculation of the H2FPEF score and were dichotomized into two groups: the low H2FPEF score [0-5 points; n = 1399 (83.6%)] group and the high H2FPEF score [6-9 points; n = 275 (16.4%)] group. Patients with high H2FPEF scores were associated with a higher prevalence of New York Heart Association Functional Class III/IV (59.3% vs. 43.7%, P < 0.001), diabetes (24.4% vs. 18.5%, P = 0.03), and paradoxical low-flow, low-gradient aortic stenosis (15.9% vs. 6.2%, P < 0.001). These patients showed worse prognoses than those with low H2FPEF scores regarding the cumulative 2 year all-cause mortality (26.3% vs. 15.5%, log-rank P < 0.001), cardiovascular mortality (10.5% vs. 5.4%, log-rank P < 0.001), HF hospitalization (16.2% vs. 6.7%, log-rank P < 0.001), and the composite endpoint of cardiovascular mortality and HF hospitalization (23.8% vs. 10.8%, log-rank P < 0.001). After adjustment for several confounders, the high H2FPEF scores were independently associated with increased risk for all-cause mortality [adjusted hazard ratio (HR), 1.48; 95% confidence interval (CI), 1.09-2.00; P = 0.011] and for the composite endpoint of cardiovascular mortality and HF hospitalization (adjusted HR, 1.95; 95% CI, 1.38-2.74; P < 0.001). Subgroup analysis confirmed the excess risk of high H2FPEF scores relative to low H2FPEF scores for the composite endpoint of cardiovascular mortality and HF hospitalization increased with a lower Society of Thoracic Surgeons (STS) score (STS score <8%: adjusted HR, 2.40; 95% CI, 1.50-3.85; P < 0.001; STS score ≥8%: adjusted HR, 1.34; 95% CI, 0.79-2.28; P = 0.28; Pinteraction = 0.030).

The H2FPEF score is useful for predicting long-term adverse outcomes after TAVI, including all-cause mortality, cardiovascular mortality, and HF hospitalization for patients with preserved EF. More aggressive interventions targeting HFpEF in addition to the TAVI procedure might be relevant in patients with high H2FPEF scores, particularly in those with a lower surgical risk.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome requiring improved phenotypic classification. Previous studies have identified subphenotypes of HFpEF, but the lack of exercise assessment is a major limitation. The aim of this study was to identify distinct pathophysiologic clusters of HFpEF based on clinical characteristics, and resting and exercise assessments.

A total of 265 patients with HFpEF underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. Cluster analysis was performed by the K-prototype method with 21 variables (10 clinical and resting echocardiographic variables and 11 exercise echocardiographic parameters). Pathophysiologic features, exercise tolerance, and prognosis were compared among phenogroups.

Three distinct phenogroups were identified. Phenogroup 1 (n = 112 [42%]) was characterized by preserved biventricular systolic reserve and cardiac output augmentation. Phenogroup 2 (n = 58 [22%]) was characterized by a high prevalence of atrial fibrillation, increased pulmonary arterial and right atrial pressures, depressed right ventricular systolic functional reserve, and impaired right ventricular-pulmonary artery coupling during exercise. Phenogroup 3 (n = 95 [36%]) was characterized by the smallest body mass index, ventricular and vascular stiffening, impaired left ventricular diastolic reserve, and worse exercise capacity. Phenogroups 2 and 3 had higher rates of composite outcomes of all-cause mortality or heart failure events than phenogroup 1 (log-rank P = .02).

Exercise echocardiography-based cluster analysis identified three distinct phenogroups of HFpEF, with unique exercise pathophysiologic features, exercise capacity, and clinical outcomes.

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly 70% of all HF and has become the dominant form of HF. The increased prevalence of HFpEF has contributed to a rise in the number of HF patients, known as the "heart failure pandemic". In addition to the fact that HF is a progressive disease and a delayed diagnosis may worsen clinical outcomes, the emergence of disease-modifying treatments such as sodium-glucose transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists has made appropriate and timely identification of HFpEF even more important. However, diagnosis of HFpEF remains challenging in patients with a lower degree of congestion. In addition to normal EF, this is related to the fact that left ventricular (LV) filling pressures are often normal at rest but become abnormal during exercise. Exercise stress echocardiography can identify such exercise-induced elevations in LV filling pressures and facilitate the diagnosis of HFpEF. Exercise stress echocardiography may also be useful for risk stratification and assessment of exercise tolerance as well as cardiovascular responses to exercise. Recent attention has focused on dedicated dyspnea clinics to identify early HFpEF among patients with unexplained dyspnea and to investigate the causes of dyspnea. This review discusses the role of exercise stress echocardiography in the diagnosis and evaluation of HFpEF.

Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We have developed a novel "2-hit" model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57BL6/NJ mice fed a high fat diet for >10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d . Control mice, HFD only, Renin only and HFD-Renin (aka "HFpEF") littermates underwent a battery of cardiac and extracardiac phenotyping. HFD-Renin mice demonstrated obesity and insulin resistance, a 2-3-fold increase in circulating renin levels that resulted in 30-40% increase in left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by altered E/e', IVRT, and strain measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to findings in human HFpEF. Treatment of these mice with the sodium-glucose cotransporter 2 inhibitor empagliflozin, an effective but incompletely understood HFpEF therapy, improved exercise tolerance, left heart enlargement, and insulin homeostasis. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Addition of HFD-Renin mice to the preclinical HFpEF model platform allows for orthogonal studies to increase validity in assessment of interventions.

Heart failure with preserved ejection fraction (HFpEF) is a complex disease to study due to limited preclinical models. We rigorously characterize a new two-hit HFpEF mouse model, which allows for dissecting individual contributions and synergy of major pathogenic drivers, hypertension and diet-induced obesity. The results are consistent and reproducible in two independent laboratories. This high-fidelity pre-clinical model increases the available, orthogonal models needed to improve our understanding of the causes and assessment treatments for HFpEF.

Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of all heart failure cases nationwide and continues to rise in its prevalence. The complex, multi-organ involvement of the HFpEF clinical syndrome requires clinicians and investigators to adopt an integrative approach that considers the contribution of both cardiac and non-cardiac function to HFpEF pathophysiology. Thus, this symposium review outlines the key points from presentations covering the contributions of disease-related changes in cardiac function, arterial stiffness, peripheral vascular function, and oxygen delivery and utilization to exercise tolerance in patients with HFpEF. While many aspects of HFpEF pathophysiology remain poorly understood, there is accumulating evidence for a decline in vascular health in this patient group that may be remediable through pharmacological and lifestyle interventions and could improve outcomes and clinical status in this ever-growing patient population.

We aimed to clarify the extent to which cardiac and peripheral impairments to oxygen delivery and utilization contribute to exercise intolerance and risk for adverse events, and how this relates to diversity and multiplicity in pathophysiologic traits.

Individuals with heart failure with preserved ejection fraction (HFpEF) and non-cardiac dyspnoea (controls) underwent invasive cardiopulmonary exercise testing and clinical follow-up. Haemodynamics and oxygen transport responses were compared. HFpEF patients were then categorized a priori into previously-proposed, non-exclusive descriptive clinical trait phenogroups, including cardiometabolic, pulmonary vascular disease, left atrial myopathy, and vascular stiffening phenogroups based on clinical and haemodynamic profiles to contrast pathophysiology and clinical risk. Overall, patients with HFpEF (n = 643) had impaired cardiac output reserve with exercise (2.3 vs. 2.8 L/min, p = 0.025) and greater reliance on peripheral oxygen extraction augmentation (4.5 vs. 3.8 ml/dl, p < 0.001) compared to dyspnoeic controls (n = 219). Most (94%) patients with HFpEF met criteria for at least one clinical phenogroup, and 67% fulfilled criteria for multiple overlapping phenogroups. There was greater impairment in peripheral limitations in the cardiometabolic group and greater cardiac output limitations and higher pulmonary vascular resistance during exertion in the other phenogroups. Increasing trait multiplicity within a given patient was associated with worse exercise haemodynamics, poorer exercise capacity, lower cardiac output reserve, and greater risk for heart failure hospitalization or death (hazard ratio 1.74, 95% confidence interval 1.08-2.79 for 0-1 vs. ≥2 phenogroup traits present).

Though cardiac output response to exercise is limited in patients with HFpEF compared to those with non-cardiac dyspnoea, the relative contributions of cardiac and peripheral limitations vary with differing numbers and types of clinical phenotypic traits present. Patients fulfilling criteria for greater multiplicity and diversity of HFpEF phenogroup traits have poorer exercise capacity, worsening haemodynamic perturbations, and greater risk for adverse outcome.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a prevalent global condition affecting approximately 50% of the HF population. With the aging of the worldwide population, its incidence and prevalence are expected to rise even further. Unfortunately, until recently, no effective medications were available to reduce the high mortality and hospitalization rates associated with HFpEF, making it a significant unmet need in cardiovascular medicine. Although HFpEF is commonly defined as HF with normal ejection fraction and elevated left ventricular filling pressure, performing invasive hemodynamic assessments on every individual suspected of having HFpEF is neither feasible nor practical. Consequently, several clinical criteria and diagnostic tools have been proposed to aid in diagnosing HFpEF. Overall, these criteria and tools are designed to assist healthcare professionals in identifying and evaluating patients who may have HFpEF based on a combination of signs, symptoms, biomarkers, and non-invasive imaging findings. By employing these non-invasive diagnostic approaches, clinicians can make informed decisions regarding the best pharmacological and rehabilitation strategies for individuals with suspected HFpEF. This literature review aims to provide an overview of all currently available methods for diagnosing and monitoring this disabling condition.

To determine whether nitrite can enhance exercise training (ET) effects in heart failure with preserved ejection fraction (HFpEF).

In this multicenter, double-blind, placebo-controlled, randomized trial conducted at 1 urban and 9 rural outreach centers between November 22, 2016, and December 9, 2021, patients with HFpEF underwent ET along with inorganic nitrite 40 mg or placebo 3 times daily. The primary end point was peak oxygen consumption (VO2). Secondary end points included Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS, range 0 to 100; higher scores reflect better health status), 6-minute walk distance, and actigraphy.

Of 92 patients randomized, 73 completed the trial because of protocol modifications necessitated by loss of drug availability. Most patients were older than 65 years (80%), were obese (75%), and lived in rural settings (63%). At baseline, median peak VO2 (14.1 mL·kg-1·min-1) and KCCQ-OSS (63.7) were severely reduced. Exercise training improved peak VO2 (+0.8 mL·kg-1·min-1; 95% CI, 0.3 to 1.2; P<.001) and KCCQ-OSS (+5.5; 95% CI, 2.5 to 8.6; P<.001). Nitrite was well tolerated, but treatment with nitrite did not affect the change in peak VO2 with ET (nitrite effect, -0.13; 95% CI, -1.03 to 0.76; P=.77) or KCCQ-OSS (-1.2; 95% CI, -7.2 to 4.9; P=.71). This pattern was consistent across other secondary outcomes.

For patients with HFpEF, ET administered for 12 weeks in a predominantly rural setting improved exercise capacity and health status, but compared with placebo, treatment with inorganic nitrite did not enhance the benefit from ET.

ClinicalTrials.gov identifier: NCT02713126.

Heart failure (HF) with normal ejection fraction - the isolated diastolic heart failure, depicts increasing prevalence and health care burden in recent times. Having less mortality rate compared to systolic heart failure but high morbidity, it is evolving as a major cardiac concern. With increasing clinical use of Left atrial volume (LAV) quantitation in clinical settings, LAV has emerged as an important independent predictor of cardiovascular outcome in HF with normal ejection fraction. This article is intended to review the diastolic and systolic heart failure, their association with left atrial volume, in depth study of Left atrial function dynamics with determinants of various functional and structural changes.

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.

Diagnosis of heart failure with preserved ejection fraction (HFpEF) can be challenging and it could require different tests, some of which are affected by limited availability. Nowadays, considering that new therapies are available for HFpEF and related conditions, a prompt and correct diagnosis is relevant. However, the diagnostic role of biomarker level, imaging tools, score-based algorithms and invasive evaluation, should be based on the strengths and weaknesses of each test. The aim of this review is to help the clinician in diagnosing HFpEF, overcoming the diagnostic uncertainty and disentangling among the different underlying causes, in order to properly treat this kind of patient.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in women in developed societies. Unfavorable structural and functional adaptations within the heart and central blood vessels with sedentary aging in women can act as the substrate for the development of debilitating CVD conditions such as heart failure with preserved ejection fraction (HFpEF). The large decline in cardiorespiratory fitness, as indicated by maximal or peak oxygen uptake (V̇o2max and V̇o2peak, respectively), that occurs in women as they age significantly affects their health and chronic disease status, as well as the risk of cardiovascular and all-cause mortality. Midlife and older women who have performed structured endurance exercise training for several years or decades of their adult lives exhibit a V̇o2max and cardiac and vascular structure and function that are on par or even superior to much younger sedentary women. Therefore, regular endurance exercise training appears to be an effective preventative strategy for mitigating the adverse physiological cardiovascular adaptations associated with sedentary aging in women. Herein, we narratively describe the aging and short- and long-term endurance exercise training adaptations in V̇o2max, cardiac structure, and left ventricular systolic and diastolic function at rest and exercise in midlife and older women. The role of circulating estrogens on cardiac structure and function is described for consideration in the timing of exercise interventions to maximize beneficial adaptations. Current research gaps and potential areas for future investigation to advance our understanding in this critical knowledge area are highlighted.

Sodium-glucose cotransporter-2 inhibitors reduce risk of hospitalization for heart failure in patients who have heart failure with preserved ejection fraction (HFpEF), but the hemodynamic mechanisms underlying these benefits remain unclear. This study sought to determine whether treatment with dapagliflozin affects pulmonary capillary wedge pressure (PCWP) at rest and during exercise in patients with HFpEF.

This was a single-center, double-blinded, randomized, placebo-controlled trial testing the effects of 10 mg of dapagliflozin once daily in patients with HFpEF. Patients with New York Heart Association class II or III heart failure, ejection fraction ≥50%, and elevated PCWP during exercise were recruited. Cardiac hemodynamics were measured at rest and during exercise using high-fidelity micromanometers at baseline and after 24 weeks of treatment. The primary end point was a change from baseline in rest and peak exercise PCWPs that incorporated both measurements, and was compared using a mixed-model likelihood ratio test. Key secondary end points included body weight and directly measured blood and plasma volumes. Expired gas analysis was performed evaluate oxygen transport in tandem with arterial lactate sampling.

Among 38 patients completing baseline assessments (median age 68 years; 66% women; 71% obese), 37 completed the trial. Treatment with dapagliflozin resulted in reduction in the primary end point of change in PCWP at rest and during exercise at 24 weeks relative to treatment with placebo (likelihood ratio test for overall changes in PCWP; P<0.001), with lower PCWP at rest (estimated treatment difference [ETD], -3.5 mm Hg [95% CI, -6.6 to -0.4]; P=0.029) and maximal exercise (ETD, -5.7 mm Hg [95% CI, -10.8 to -0.7]; P=0.027). Body weight was reduced with dapagliflozin (ETD, -3.5 kg [95% CI, -5.9 to -1.1]; P=0.006), as was plasma volume (ETD, -285 mL [95% CI, -510 to -60]; P=0.014), but there was no significant effect on red blood cell volume. There were no differences in oxygen consumption at 20-W or peak exercise, but dapagliflozin decreased arterial lactate at 20 W (-0.70 ± 0.77 versus 0.37 ± 1.29 mM; P=0.006).

In patients with HFpEF, treatment with dapagliflozin reduces resting and exercise PCWP, along with the favorable effects on plasma volume and body weight. These findings provide new insight into the hemodynamic mechanisms of benefit with sodium-glucose cotransporter-2 inhibitors in HFpEF.

URL: https://www.

gov; Unique identifier: NCT04730947.