Harada, Tomonari

Abstract Background Systemic arterial compliance and venous capacitance are typically impaired in patients with heart failure with preserved ejection fraction (HFpEF), contributing to hemodynamic congestion with stress. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce hemodynamic congestion and improve clinical outcomes in patients with HFpEF, but the mechanisms remain unclear. Purpose This study tested the hypothesis that SGLT2i dapagliflozin would improve systemic arterial compliance and venous capacitance during exercise in patients with HFpEF. Methods In this secondary analysis from the RCT trial, patients with HFpEF underwent invasive hemodynamic exercise testing at baseline and following treatment for 24 weeks with dapagliflozin or placebo. Patients were required to display pulmonary capillary wedge pressure (PCWP) ≥25 mmHg during exercise at the time of baseline evaluation. Radial artery pressure (BP) was measured continuously using a fluid-filled catheter with transformation to aortic pressure, central hemodynamics were measured using high-fidelity micromanometers, and stressed blood volume was estimated (eSBV) from hemodynamic indices fit to a comprehensive cardiovascular model. Results A total of 37 patients completed the study and were included in this analysis (21 dapagliflozin and 16 placebo). Patients were predominantly women (24/37, 65%) and older (mean age 67 years). There was no statistically significant effect of dapagliflozin on resting BP, but dapagliflozin reduced systolic BP during peak exercise (estimated treatment difference [ETD], -18.8 mmHg, 95% CI: -33.9 to -3.7, P=0.016) (Figure 1A). Dapagliflozin improved exertional total arterial compliance (TAC) index (ETD, 0.06 mL/mmHg/m2, 95% CI: 0.003 to 0.11, P=0.039) (Figure 1B) and aortic root characteristic impedance (ETD, -2.6 mmHg/ml*sec, 95% CI: -5.1 to -0.03, P=0.048) during peak exercise, with no significant effect on systemic vascular resistance. Dapagliflozin reduced eSBV at rest and during peak exercise (ETD, -292 mmHg, 95% CI: -530 to -53, P=0.018) (Figure 1C), and improved venous capacitance evidenced by a decline in ratio of eSBV to total blood volume (ETD, -7.3%, 95% CI -13.3 to -1.3, P=0.020). Each of these effects of dapagliflozin during peak exercise were also observed during matched 20W exercise intensity. Improvements in TAC index and eSBV were correlated with decreases in body weight, and reduction in systolic BP with treatment was correlated with the change in eSBV during exercise (r=0.40, P=0.019) (Figure 2A). Decreases in BP were correlated with reduction in PCWP during exercise (r=0.56, P<0.001) (Figure 2B). Conclusion In patients with HFpEF, treatment with dapagliflozin improved systemic arterial compliance and venous capacitance during exercise, while reducing aortic characteristic impedance, suggesting a reduction in arterial wall stiffness. These vascular effects may partially explain the clinical benefits with SGLT2i in HFpEF.

Abstract Background Inflammation plays a fundamental role in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFpEF). In most patients, inflammation develops secondary to cardiometabolic comorbidities, but in some, HFpEF develops in the setting of underlying systemic inflammatory diseases represented by rheumatoid arthritis. Purpose This study aimed to investigate the prevalence, pathophysiology, and outcome of patients with HFpEF and primary inflammatory diseases. Methods Consecutive patients undergoing hemodynamic exercise testing with concurrent expiratory gas analysis to evaluate dyspnea of unknown cause were identified. HFpEF was defined as left ventricular ejection fraction ≥50% and pulmonary capillary wedge pressure ≥15 mmHg (rest) or ≥25 mmHg (exercise). Patients with HFpEF were divided into groups with and without primary inflammatory diseases. Patients without inflammatory disease were divided into tertiles according to the value of C-reactive protein (CRP). Results Of 982 consecutively evaluated patients with HFpEF diagnosed (577 female, mean age 68 years), 79 (8%) had primary inflammatory disease. In multivariable logistic regression, female sex (OR 1.88; 95% CI 1.01-3.52), higher resting heart rate (OR 1.18; 95% CI 1.08-1.30), lower hemoglobin level (OR 0.84; 95% CI 0.70-0.99), absence of history of atrial fibrillation (OR 0.45; 95% CI 0.24-0.86) and absence of epicardial coronary artery disease (OR 0.45; 95% CI 0.22-0.93) were independently associated with inflammatory disease. Hemodynamics at rest and exercise did not differ between the groups, but peripheral oxygen extraction was lower in those with inflammatory disease, reflected by lower arterial-venous oxygen content difference (Ca-vO2) at rest (4.2±0.7 mL/dL vs 4.6±1.0 mL/dL, P<.001) and during exercise (9.3±2.2 mL/dL vs 10.4±2.2 mL/dL, P<.001) (Figure 1A), suggesting a greater peripheral deficit, and ventilatory efficiency (VE/VCO2 slope) was also more impaired (38.0±7.9 vs 36.2±7.3, P=.035). The HFpEF patients without inflammatory disease falling in the highest tertile of CRP) displayed lower Ca-vO2 during exercise, more closely resembling peripheral deficits observed in those with inflammatory disease (Figure 1B). During a median follow-up of 3.0 years, the composite outcome of all-cause deaths and HF hospitalization occurred in 127 patients (14%). Patients with HFpEF and inflammatory disease showed a higher incidence of composite outcome than those without (log-rank P=.030; Figure 2). Patients with inflammatory disease had higher risk of composite outcome compared to those without in adjusted analyses (HR 1.93; 95% CI 1.15-3.23), which was primarily attributable to higher risk of HF hospitalization (HR 2.85; 95% CI 1.08-7.52). Conclusion Patients with HFpEF and primary inflammatory disease have similar hemodynamic derangements but greater peripheral deficits in oxygen transport and higher risk for adverse outcome compared to those without.

Abstract Aims The diagnostic difficulty of heart failure with preserved ejection fraction (HFpEF) is related to the fact that many patients develop abnormal hemodynamics only during exercise. Exercise stress echocardiography is a first-line test to unmask such abnormalities, but exercise protocols and diagnostic criteria have not been established. It remains unclear how cardiologists diagnose HFpEF by exercise echocardiography in real-world practice. Methods and Results An international web-based survey was performed on 87 cardiologists, 59% of whom had ≥ 6 years of experience with exercise echocardiography. A retrospective cohort of 652 dyspneic patients who underwent exercise echocardiography was used to determine the impact of different diagnostic criteria on the proportion of HFpEF diagnosis. The most commonly used exercise echocardiography criterion for the HFpEF diagnosis was the HFA-PEFF algorithm (48%), followed by the ASE/EACVI criteria (24%) and some combinations of multiple parameters (22%). A retrospective study found that the proportion of HFpEF diagnosis varied substantially between the criteria used: 20.1% for the ASE/EACVI criteria and 44.3% for the HFA-PEFF algorithm. A survey demonstrated that 54% of the participating cardiologists would initiate sodium-glucose co-transporter 2 inhibitors based on exercise echocardiography results. Conclusion In real-world practice, exercise echocardiography criteria for HFpEF diagnosis vary among cardiologists. While many cardiologists consider initiating pharmacological treatment on exercise echocardiography results, the frequency of HFpEF diagnosis varies substantially depending on the diagnostic criteria used. The lack of universal diagnostic criteria may limit the delivery of evidence-based treatment to patients with HFpEF.

Abstract Background Excess fat, particularly visceral fat, plays an important role in the development of heart failure with preserved ejection fraction (HFpEF). Sodium glucose cotransporter-2 inhibitors improve hemodynamics, reduce symptom severity, and decrease risk of hospitalization, but their impact on body composition, as well as potential relationships between changes in body composition and hemodynamic effects, are unknown in HFpEF. Purpose Evaluate the effect of dapagliflozin on body and blood composition and examined the potential correlation of such changes on cardiac hemodynamics. Methods The CAMEO-DAPA trial, a single-center, double-blind, randomized, placebo-controlled study, showed that 24 weeks of dapagliflozin reduced resting and exercise pulmonary capillary wedge pressures (PCWP) in patients with HFpEF. This prespecified secondary analysis reports the effects of dapagliflozin on body composition using dual energy x-ray absorptiometry (DEXA), blood composition (radiolabeled iodinated albumin), and cardiac hemodynamics using high-fidelity micromanometers. Analysis was performed based on the intention-to-treat. Relative change was calculated by dividing the absolute change on the baseline value. Results Overall, 37 patients (67 years, 65% women, 70% with obesity, 27% overweight) completed the trial. As compared with baseline, dapagliflozin decreased total body fat compared with placebo [mean (SD) absolute change: -2.29 (2.94) kg vs -0.32 (1.84) in placebo, p=0.03; relative change: -4.6% (5.4) vs -0.8% (4.3), p=0.02], Figure 1. This was primarily due to greater loss of upper body trunk fat [absolute change: -1.53 (1.70) kg vs +0.31 (0.99) in placebo, p<.001; relative change: -5.2% (5.6) vs +1.1% (4.1), p<.001], Figure 1. Reductions in trunk fat were correlated with decreases in PCWP (r=0.41, p=0.03), Figure 2. Total body fat-free mass (FFM) tended to decrease in the dapagliflozin group [absolute change: -0.63 (1.85) kg vs +0.34 (1.76), p=0.12]; reductions in leg, android, and gynoid FFM were all greater than placebo (p<0.05). Dapagliflozin reduced plasma volume [absolute change: -170 (343) ml vs +112 (346), p=0.02] compared with placebo, and the decrease in plasma volume was correlated with the reduction in FFM (r=0.47, p=0.006), Figure 2. Treatment with dapagliflozin had no effect on resting metabolic rate but was associated with modest reduction in bone mineral content [-16 (47) g vs +26 (61), p=0.03]. Conclusions In patients with HFpEF, dapagliflozin decreases body fat, particularly trunk fat, suggesting greater effect on visceral adipose, which is correlated with favorable hemodynamic effects. Dapagliflozin also tends to reduce FFM, which may relate to reduction in total body water with or without reduction is muscle mass, in tandem with modest decreases in bone mineral content.Figure 1:Relative change in fat massFigure 2

BACKGROUND: Systemic arterial compliance and venous capacitance are typically impaired in patients with heart failure with preserved ejection fraction (HFpEF), contributing to hemodynamic congestion with stress. Sodium-glucose cotransporter-2 inhibitors reduce hemodynamic congestion and improve clinical outcomes in patients with HFpEF, but the mechanisms remain unclear. This study tested the hypothesis that Dapagliflozin would improve systemic arterial compliance and venous capacitance during exercise in patients with HFpEF. METHODS: In this secondary analysis from the CAMEO-DAPA trial (Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial), 37 patients with HFpEF (mean age 68 ± 9 years, women 65%) underwent invasive hemodynamic exercise testing with simultaneous echocardiography at baseline and following treatment for 24 weeks with Dapagliflozin or placebo. Radial artery pressure (BP) was measured continuously using a fluid-filled catheter with transformation to aortic pressure, central hemodynamics were measured using high-fidelity micromanometers, and stressed blood volume was estimated from hemodynamic indices fit to a comprehensive cardiovascular model. RESULTS: There was no statistically significant effect of Dapagliflozin on resting BP, but Dapagliflozin reduced systolic BP during peak exercise (estimated treatment difference [ETD], −18.8 mm Hg [95% CI, −33.9 to −3.7] P =0.016). Reduction in BP was related to improved exertional total arterial compliance (ETD, 0.06 mL/mm Hg/m 2 [95% CI, 0.003–0.11] P =0.039) and aortic root characteristic impedance (ETD, −2.6 mm Hg/mL*sec [95% CI: −5.1 to −0.03] P =0.048), with no significant effect on systemic vascular resistance. Dapagliflozin reduced estimated stressed blood volume at rest and during peak exercise (ETD, −292 mm Hg [95% CI, −530 to −53] P =0.018), and improved venous capacitance evidenced by a decline in ratio of estimated stressed blood volume to total blood volume (ETD, −7.3% [95% CI, −13.3 to −1.3] P =0.020). Each of these effects of Dapagliflozin at peak exercise were also observed during matched 20W exercise intensity. Improvements in total arterial compliance and estimated stressed blood volume were correlated with decreases in body weight, and reduction in systolic BP with treatment was correlated with the change in estimated stressed blood volume during exercise (r=0.40, P =0.019). Decreases in BP were correlated with reduction in pulmonary capillary wedge pressure during exercise (r=0.56, P <0.001). CONCLUSIONS: In patients with HFpEF, treatment with Dapagliflozin improved systemic arterial compliance and venous capacitance during exercise, while reducing aortic characteristic impedance, suggesting a reduction in arterial wall stiffness. These vascular effects may partially explain the clinical benefits with sodium-glucose cotransporter-2 inhibitors in HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04730947.

Abstract Understanding of the pathophysiology of heart failure with preserved ejection fraction (HFpEF) has advanced rapidly over the past two decades. Currently, HFpEF is recognized as a heterogeneous syndrome, and there is a growing movement towards developing personalized treatments based on phenotype-guided strategies. Left ventricular dysfunction is a fundamental pathophysiological abnormality in HFpEF; however, recent evidence also highlights significant roles for the atria, right ventricle, pericardium, and extracardiac contributors. Imaging plays a central role in characterizing these complex and highly integrated domains of pathophysiology. This review focuses on established evidence, recent insights, and the challenges that need to be addressed concerning the pathophysiology of HFpEF, with a focus on imaging-based evaluations and opportunities for further research.

Abstract Aims The diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging based on resting assessments. Exercise echocardiography is often used to unmask abnormalities that develop during exercise, but the diagnostic criteria have not been standardized. This study aimed to elucidate how cardiologists utilize exercise echocardiography to diagnose HFpEF in real-world practice. Methods and results An international web-based survey involving 87 cardiologists was performed. We also performed a retrospective cross-sectional study to investigate the impact of different exercise echocardiographic diagnostic criteria in 652 dyspnoeic patients who underwent exercise echocardiography. The HFA-PEFF algorithm was the most commonly used exercise echocardiography criterion for HFpEF diagnoses (48%), followed by the ASE/EACVI criteria (24%) and other combinations of multiple parameters (22%). Among 652 patients, the proportion of HFpEF diagnosis varied substantially according to the criteria used ranging from 20.1% (ASE/EACVI criteria) to 44.3% (HFA-PEFF algorithm). Many cases (49.4–70.5%) remained indeterminate after exercise echocardiography, but only 41% of surveyed cardiologists would utilize exercise right heart catheterization to resolve an indeterminate result. Despite these diagnostic uncertainties, 54% of surveyed cardiologists would utilize exercise echocardiography results to initiate sodium–glucose co-transporter 2 inhibitors. Conclusion In real-world practice, exercise echocardiographic criteria utilized across cardiologists vary, which meaningfully impacts the frequency of HFpEF diagnoses, with indeterminate results being common. Despite these diagnostic uncertainties, many cardiologists initiate pharmacotherapy based on exercise echocardiography. The lack of consensus on universal diagnostic criteria for exercise echocardiography and approaches to indeterminate results may limit the delivery of evidence-based treatment for HFpEF.

Abstract Aims This study aimed to evaluate the clinical significance of secondary mitral regurgitation (MR) in patients with heart failure with preserved ejection fraction (HFpEF). Methods and results We conducted a prospective study enrolling consecutively evaluated patients with HFpEF undergoing invasive haemodynamic exercise testing with simultaneous echocardiography. Compared to HFpEF without MR (n = 145, 79.7%), those with mild or moderate MR (n = 37, 20.3%) were older, more likely to be women, had more left ventricular (LV) systolic dysfunction, and more likely to have left atrial (LA) myopathy reflected by greater burden of atrial fibrillation, more LA dilatation, and poorer LA function. Pulmonary artery (PA) wedge pressure was higher at rest in HFpEF with MR (17 ± 5 mmHg vs. 20 ± 5 mmHg, p = 0.005), but there was no difference with exercise. At rest, only 2 (1.1%) patients had moderate MR, and none developed severe MR. Pulmonary vascular resistance was higher, and right ventricular (RV)-PA coupling was more impaired in patients with HFpEF and MR at rest and exercise. LV and LA myocardial dysfunction remained more severe in patients with MR during stress compared to those without MR, characterized by greater LA dilatation during all stages of exertion, lower LA emptying fraction and compliance, steeper and rightward-shifted LA pressure–volume relationships, and reduced LV longitudinal contractile function. Conclusions Patients with HFpEF and mild or moderate MR have more severe LV systolic dysfunction, LA myopathy, RV-PA uncoupling, and more severe pulmonary vascular disease. Mitral valve incompetence in this setting is a phenotypic marker of more advanced disease but is not a causal factor in development of HFpEF.