Objectives To comprehensively examine cardiovascular reserve function with exercise in patients with heart failure and preserved ejection fraction (HFpEF). Background Optimal exercise performance requires an integrated physiologic response, with coordinated increases in heart rate, contractility, lusitropy, arterial vasodilatation, endothelial function and venous return. Cardiac and vascular responses are coupled, and abnormalities in several components may interact to promote exertional intolerance in HFpEF. Methods Subjects with HFpEF (n=21), hypertension without heart failure (n=19) and no cardiovascular disease (control, n=10) were studied before and during exercise with characterization of cardiovascular reserve function by Doppler echocardiography, peripheral arterial tonometry and gas exchange. Results Exercise capacity and tolerance were reduced in HFpEF compared with hypertensives and controls, with lower VO2 and cardiac index at peak, and more severe dyspnea and fatigue at matched low-level workloads. Endothelial function was impaired in HFpEF and in hypertensives as compared with controls. However, blunted exercise-induced increases in chronotropy, contractility and vasodilation were unique to HFpEF and resulted in impaired dynamic ventricular-arterial coupling responses during exercise. Exercise capacity and symptoms of exertional intolerance were correlated with abnormalities in each component of cardiovascular reserve function, and HFpEF subjects were more likely to display multiple abnormalities in reserve. Conclusion HFpEF is characterized by depressed reserve capacity involving multiple domains of cardiovascular function, which contribute in an integrated fashion to produce exercise limitation. Appreciation of the global nature of reserve dysfunction in HFpEF will better inform optimal design for future diagnostic and therapeutic strategies.

Background Diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF) is challenging and relies largely on demonstration of elevated cardiac filling pressures (pulmonary capillary wedge pressure, PCWP). Current guidelines recommend use of natriuretic peptides (NT-proBNP) and rest/exercise echocardiography (E/e’ ratio) to make this determination. Data to support this practice is conflicting. Methods Simultaneous echocardiographic-catheterization studies were prospectively conducted at rest and during exercise in subjects with invasively-proven HFpEF (n=50) and participants with dyspnea but no identifiable cardiac pathology (n=24). Results NT-proBNP levels were below the level considered to exclude disease (≤125 pg/ml) in 18% of subjects with HFpEF. E/e’ ratio was correlated with directly measured PCWP at rest (r=0.63, p<0.0001) and during exercise (r=0.57, p<0.0001). While specific, current guidelines were poorly sensitive, identifying only 34–60% of subjects with invasively-proven HFpEF based upon resting echocardiographic data alone. Addition of exercise echocardiographic data (E/e’ ratio>14) improved sensitivity (to 90%) and thus negative predictive value, but decreased specificity (71%). Conclusions Currently proposed HFpEF diagnostic guidelines based upon resting data are poorly sensitive. Adding exercise E/e’ data improves sensitivity and negative predictive value but compromises specificity, suggesting that exercise echocardiography may help rule out HFpEF. These results question the accuracy of current approaches to exclude HFpEF based upon resting data alone and reinforce the value of exercise testing using invasive and noninvasive hemodynamic assessments to definitively confirm or refute the diagnosis of HFpEF. Clinical trial registration NCT01418248 https://clinicaltrials.gov/ct2/results?term=NCT01418248&Search=Search

In addition to limited LV reserve, patients with HFpEF display impaired RV reserve during exercise that is associated with high filling pressures and inadequate CO responses. These findings highlight the importance of biventricular dysfunction in HFpEF and suggest that novel therapies targeting myocardial reserve in both the left and right heart may be effective to improve clinical status.

AimsExercise intolerance is a hallmark of heart failure with preserved ejection fraction (HFpEF), yet its mechanisms remain unclear. The current study sought to determine whether increases in cardiac output (CO) during exercise are appropriately matched to metabolic demands in HFpEF. Methods and resultsPatients with HFpEF (n ¼ 109) and controls (n ¼ 73) exercised to volitional fatigue with simultaneous invasive (n ¼ 96) or non-invasive (n ¼ 86) haemodynamic assessment and expired gas analysis to determine oxygen consumption (VO 2 ) during upright or supine exercise. At rest, HFpEF patients had higher LV filling pressures but similar heart rate, stroke volume, EF, and CO. During supine and upright exercise, HFpEF patients displayed lower peak VO 2 coupled with blunted increases in heart rate, stroke volume, EF, and CO compared with controls. LV filling pressures increased dramatically in HFpEF patients, with secondary elevation in pulmonary artery pressures. Reduced peak VO 2 in HFpEF patients was predominantly attributable to CO limitation, as the slope of the increase in CO relative to VO 2 was 20% lower in HFpEF patients (5.9 + 2.5 vs. 7.4 + 2.6 L blood/L O 2 , P ¼ 0.0005). While absolute increases in arterial -venous O 2 difference with exercise were similar in HFpEF patients and controls, augmentation in arterial-venous O 2 difference relative to VO 2 was greater in HFpEF patients (8.9 + 3.4 vs. 5.5 + 2.0 min/dL, P , 0.0001). These differences were observed in the total cohort and when upright and supine exercise modalities were examined individually. ConclusionWhile diastolic dysfunction promotes congestion and pulmonary hypertension with stress in HFpEF, reduction in exercise capacity is predominantly related to inadequate CO relative to metabolic needs.--