Background: Exercise‐induced high heart rate may impair exercise tolerance by reducing diastolic filling time and ventricular filling in heart failure with preserved ejection fraction (HFpEF). Given the importance of chronotropic response, we hypothesized that reduction in diastolic filling time because of exercise‐induced increased heart rate would not impair cardiac output reserve and exercise capacity. We sought to determine the association between heart rate, diastolic filling time, hemodynamics, and exercise capacity in HFpEF. Methods and Results: Patients with HFpEF (n=66) and controls without HF (n=107) underwent bicycle exercise echocardiography with simultaneous expired gas analysis to measure oxygen consumption. Diastolic filling time was assessed by the overlap time between mitral E‐ and A‐waves (longer overlap time indicates shorter diastolic filling duration). Overlap time increased (ie, diastolic filling time shortened) in HFpEF and controls as heart rate increased with exercise, and the relationship was similar between the groups. Greater heart rate response correlated with higher cardiac output ( r =0.51, P <0.0001) and oxygen consumption ( r =0.50, P <0.0001) during peak exercise. Shorter diastolic filling time, as assessed by longer overlap time, was correlated with higher cardiac output ( r =0.47, P <0.0001) and peak oxygen consumption ( r =0.38, P =0.007), not with E/e′ or right ventricular‐pulmonary artery uncoupling. Longer overlap time was associated with mitral A velocity ( r =0.53, P <0.0001) and left atrial booster pump strain ( r =0.42, P <0.0001). Conclusions: Shortening of diastolic filling interval in tandem with increased heart rate during exercise does not limit cardiac output reserve or exercise capacity in HFpEF.

BACKGROUND: Left atrial (LA) dysfunction is common in heart failure (HF) with preserved ejection fraction. However, data on the pathophysiologic impacts of impaired LA functional reserve remained limited. We sought to determine the association of abnormal LA dynamics during exercise with cardiovascular reserve, exercise capacity, and clinical outcomes. METHODS: Patients with HF with preserved ejection fraction (n=231) and controls without HF (n=219) underwent exercise stress echocardiography with simultaneous expired gas analysis. LA function was assessed at rest and during exercise using speckle-tracking echocardiography. RESULTS: Patients with HF with preserved ejection fraction demonstrated less increase in LA reservoir and booster pump strain during exercise than those in controls. The degree of LA dilation was more closely related to exercise LA reservoir strain than to resting LA strain (Meng test, P =0.002). The presence of impaired LA reservoir strain during exercise was associated with poorer biventricular systolic reserve and cardiac output augmentation, more severe right ventricular-pulmonary artery uncoupling, and lower peak oxygen consumption. Patients with a lower exercise LA reservoir strain had a 2.7-fold increased risk of HF events (hazard ratio, 2.66 [95% CI, 1.32–5.38]; P =0.006). Among patients with follow-up echocardiography, initiation of guideline-directed medical therapy or atrial fibrillation ablation showed significant improvements in LA reservoir ( P <0.001 and P =0.022) and booster pump strain ( P =0.011 and 0.028) at rest and during exercise, respectively. CONCLUSIONS: Impaired LA reservoir function during exercise in HF with preserved ejection fraction is associated with biventricular reserve limitations, exercise intolerance, and increased risks of HF events.

More than half of patients with heart failure have a preserved ejection fraction (HFpEF). The prevalence of HFpEF has been increasing worldwide and is expected to increase further, making it an important health-care problem. The diagnosis of HFpEF is straightforward in the presence of obvious objective signs of congestion; however, it is challenging in patients presenting with a low degree of congestion because abnormal elevation in intracardiac pressures may occur only during physiological stress conditions, such as during exercise. On the basis of this hemodynamic background, current consensus guidelines have emphasized the importance of exercise stress testing to reveal abnormalities during exercise, and exercise stress echocardiography (i.e., diastolic stress echocardiography) may be used as an initial diagnostic approach to HFpEF owing to its noninvasive nature and wide availability. However, evidence supporting the use of this method remains limited and many knowledge gaps exist with respect to diastolic stress echocardiography. This review summarizes the current understanding of the use of diastolic stress echocardiography in the diagnostic evaluation of HFpEF and discusses its strengths and limitations to encourage future studies on this subject.

Background: Sarco/endoplasmic reticulum Ca²⁺-ATPase2 (SERCA2) is impaired in various organs in animal models of diabetes. The purpose of this study was to test the effects of an allosteric SERCA2 activator (CDN1163) on glucose intolerance, hepatosteatosis, skeletal muscle function, and endothelial dysfunction in diabetic (db/db) mice. Methods: Either CDN1163 or vehicle was injected intraperitoneally into 16-week-old male control and db/db mice for 5 consecutive days. Results: SERCA2 protein expression was decreased in the aorta of db/db mice. In isometric tension measurements of aortic rings from db/db mice treated with CDN1163, acetylcholine (ACh)-induced relaxation was improved. In vivo intraperitoneal administrations of CDN 1163 also increased ACh-induced relaxation. Moreover, CDN1163 significantly decreased blood glucose in db/db mice at 60 and 120 min during a glucose tolerance test; it also decreased serum insulin levels, hepatosteatosis, and oxygen consumption in skeletal muscle during the early period of exercise in db/db mice. Conclusions: CDN1163 directly improved aortic endothelial dysfunction in db/db mice. Moreover, CDN1163 improved hepatosteatosis, skeletal muscle function, and insulin resistance in db/db mice. The activation of SERCA2 might be a strategy for the all the tissue expressed SERCA2a improvement of endothelial dysfunction and the target for the organs related to insulin resistance.

Aims: Exercise stress echocardiography (ESE) is often used to identify heart failure with preserved ejection fraction (HFpEF) in patients presenting dyspnoea. However, diagnostic criteria have not been standardized. Here, we sought to develop ESE-based criteria to diagnose HFpEF in dyspnoeic patients. Methods and results: A total of 81 consecutive patients with dyspnoea who underwent exercise right heart catheterization and ESE were evaluated. Diagnosis of HFpEF was ascertained by directly-measured haemodynamics (61 HFpEF and 20 controls). Logistic regression analysis was applied to develop an ESE-based scoring system to diagnose HFpEF. Multivariable logistic regression analysis identified resting left atrial reservoir strain < 20%, exercise septal E/e′ ratio > 13, and increases in ultrasound B-lines as independent predictors of HFpEF. A weighted score was created with these variables (the ESE score) ranging from 0 to 5. The ESE score accurately discriminated HFpEF from controls [area under the curve (AUC) 0.90, P < 0.0001], with a superior diagnostic ability to the ASE/ESCVI criteria (AUC comparison P < 0.0001). The ESE score classified the HFpEF probability into three categories (probabilities: low risk 28%, intermediate risk 59–83%, and high risk 95–99%). In a cohort of 620 dyspnoeic patients, the predictive ability of the derived score was assessed. A higher ESE score was associated with an increased risk of all-cause mortality or worsening HF events even after adjusting for confounders (hazard ratio; 1.17 per 1-point increase, 95% confidence intervals; 1.00–1.37, P = 0.04). Conclusion: The ESE score, which is based on three echocardiographic variables, may be an effective tool for diagnosing HFpEF on exercise echocardiography.

Background: Metabolic syndrome is characterized by insulin resistance, which impairs intracellular signaling pathways and endothelial NO bioactivity, leading to cardiovascular complications. Extracellular signal‐regulated kinase (ERK) is a major component of insulin signaling cascades that can be activated by many vasoactive peptides, hormones, and cytokines that are elevated in metabolic syndrome. The aim of this study was to clarify the role of endothelial ERK2 in vivo on NO bioactivity and insulin resistance in a mouse model of metabolic syndrome. Methods and Results: Control and endothelial‐specific ERK2 knockout mice were fed a high‐fat/high‐sucrose diet (HFHSD) for 24 weeks. Systolic blood pressure, endothelial function, and glucose metabolism were investigated. Systolic blood pressure was lowered with increased NO products and decreased thromboxane A2/prostanoid (TP) products in HFHSD‐fed ERK2 knockout mice, and Nω‐nitro‐l‐arginine methyl ester (L‐NAME) increased it to the levels observed in HFHSD‐fed controls. Acetylcholine‐induced relaxation of aortic rings was increased, and aortic superoxide level was lowered in HFHSD‐fed ERK2 knockout mice. S18886, an antagonist of the TP receptor, improved endothelial function and decreased superoxide level only in the rings from HFHSD‐fed controls. Glucose intolerance and the impaired insulin sensitivity were blunted in HFHSD‐fed ERK2 knockout mice without changes in body weight. In vivo, S18886 improved endothelial dysfunction, systolic blood pressure, fasting serum glucose and insulin levels, and suppressed nonalcoholic fatty liver disease scores only in HFHSD‐fed controls. Conclusions: Endothelial ERK2 increased superoxide level and decreased NO bioactivity, resulting in the deterioration of endothelial function, insulin resistance, and steatohepatitis, which were improved by a TP receptor antagonist, in a mouse model of metabolic syndrome.