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Background Hypertension is a frequent risk factor for the development of heart failure with preserved ejection fraction ( HFPEF ). Progressive extracellular matrix accumulation has been presumed to be the fundamental pathophysiologic mechanism that leads to the transition to impaired diastolic reserve. However, the contribution of other mechanisms affecting active and passive components of diastolic function has not been comprehensively assessed. In this study, we investigated the potential role of impaired myocardial oxygen delivery in the pathophysiology of HFPEF . Methods and Results Patients with HFPEF , those with controlled hypertension, and healthy controls underwent simultaneous right‐heart catheterization, echocardiography, and paired arterial and coronary sinus blood gas sampling at rest and during supine‐cycle ergometry. Despite a lower workload ( HFPEF vs control, hypertension: 43±8 versus 114±12, 87±14 W; P <0.001 and P <0.05, respectively), peak exercise pulmonary capillary wedge pressure was markedly higher in HFPEF patients compared with healthy and hypertensive controls (32±2 versus 16±1 and 17±1 mm Hg, both P <0.001). During exercise, the transcardiac oxygen gradient increased significantly in all groups; however, the peak transcardiac oxygen gradient was significantly lower in HFPEF patients ( P <0.05). In addition, the left ventricular–work corrected transcardiac oxygen gradient remained significantly lower in HFPEF patients compared with controls ( P <0.001). Conclusion The current study provides unique data suggesting that the abnormal diastolic reserve observed during exertion in HFPEF patients may, in part, be explained by impaired myocardial oxygen delivery due possibly to microvascular dysfunction. Further studies are required to confirm the structural and functional basis of these findings and to investigate the influence of potential therapies on this abnormality.

Abstract Aims Left ventricular systolic elastance (Ees) and diastolic elastance (Eed) correlate with arterial elastance (Ea), but it is unknown how chronic changes in arterial compliance and resistance, which determine Ea, might differentially affect cardiac properties with ageing. We sought to characterize chronic changes in pulsatile and resistive arterial load and correlate them with longitudinal changes in LV structure and function in a prospective, community-based study. Methods and results Comprehensive echocardiography was performed in 722 subjects participating in a randomly selected community-based study at two examinations separated by 4 years, allowing for assessment of LV Ees, Eed, and end-diastolic volume (EDV), Ea, total arterial compliance, and systemic vascular resistance at both examinations. Chronic changes in resistance and heart rate were the dominant contributors to change in Ea. Changes in arterial compliance had little impact on changes in Ea, but were strongly associated with changes in Ees. The combination of increased resistance and decreased compliance was associated with the largest increase in LV diastolic stiffness, an effect that was mediated by a decrease in LVEDV. In contrast, subjects with both improved arterial compliance and decreased resistance displayed an increase in LVEDV over time, with no increase in LV Eed. Conclusion Increases in pulsatile arterial load with ageing contribute more to LV systolic stiffening, while combined pulsatile and resistive loading changes are associated with positive and negative chamber remodelling and diastolic stiffness. Therapies designed to improve arterial resistance and particularly to enhance aortic compliance may hold promise to prevent or reverse cardiac ageing and its sequelae.

Background— Invasive hemodynamic exercise testing is commonly used in the evaluation of patients with suspected heart failure with preserved ejection fraction (HFpEF) or pulmonary hypertension. Saline loading has been suggested as an alternative provocative maneuver, but the hemodynamic changes induced by the 2 stresses have not been compared. Methods and Results— Twenty-six subjects (aged, 67±10 years; n=14 HFpEF; n=12 control) underwent right heart catheterization at rest, during supine exercise, and with acute saline loading in a prospective study. Exercise and saline each increased cardiac output and pressures in the right atrium, pulmonary artery, and pulmonary capillary wedge positions. Changes in heart rate, blood pressure, rate–pressure product, and cardiac output were greater with exercise compared with saline. In controls subjects, right atrial pressure, pulmonary arterial pressure, and pulmonary capillary wedge pressure increased similarly with saline and exercise, whereas in HFpEF subjects, exercise led to ≈2-fold greater increases in right atrial pressure (10±4 versus 6±3 mm Hg; P =0.02), pulmonary arterial pressure (22±8 versus 11±4 mm Hg; P =0.0001), and pulmonary capillary wedge pressure (18±5 versus 10±4 mm Hg; P <0.0001) compared with saline. Systolic reserve assessed by stroke work and cardiac power output was lower in HFpEF subjects with both exercise and saline. Systemic and pulmonary arterial compliances were enhanced with saline but reduced with exercise. Conclusions— Exercise elicits greater pulmonary capillary wedge pressure elevation compared with saline in HFpEF but not controls, suggesting that hemodynamic stresses beyond passive stiffness and increased venous return explain the development of pulmonary venous hypertension in HFpEF. Exercise testing is more sensitive than saline loading to detect hemodynamic derangements indicative of HFpEF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01418248.

Background— Patients with severe tricuspid regurgitation (TR) frequently present with exertional fatigue and dyspnea, but the hemodynamic basis for exercise limitation in people with TR remains unclear. Methods and Results— Twelve subjects with normal left ventricular (LV) ejection fraction and grade ≥3 TR underwent high-fidelity invasive hemodynamic exercise testing with simultaneous expired gas analysis and were compared with 13 age- and sex-matched controls. At rest, TR subjects had lower pulmonary blood flow (3.6±0.4 versus 5.1±1.9 L/min; P =0.01), increased right atrial pressure (12±5 versus 4±1 mm Hg; P =0.0002), and higher pulmonary capillary wedge pressure (17±5 versus 9±3 mm Hg; P =0.0001). However, LV transmural pressure (pulmonary capillary wedge pressure−right atrial pressure), which reflects LV preload independent of right heart congestion and pericardial restraint, was similar in TR and controls (6±3 versus 4±2 mm Hg; P =0.3). With exercise, TR subjects displayed lower peak V O 2 (10.3±2.8 versus 13.8±4.2 mL/min per kg; P =0.02), lower pulmonary blood flow (6.4±1.3 versus 10.3±3.3 L/min; P =0.001), and less increase in pulmonary blood flow relative to V O 2 (+4.6±1.1vs +6.2±0.7; P =0.001). TR subjects displayed higher pulmonary capillary wedge pressure with exercise, but this was solely because of RA hypertension (27±9 versus 8±3 mm Hg; P <0.0001), because LV transmural pressure dropped with exercise in subjects with TR (−5±6 versus +3±3 mm Hg; P =0.0007), suggesting inadequate LV diastolic filling, despite high pulmonary capillary wedge pressure. Conclusions— Impaired exercise capacity in people with severe TR is related to low cardiac output reserve relative to metabolic needs, coupled with elevated systemic and pulmonary venous pressures. Left heart pressures are elevated with exercise in subjects with TR, despite low LV preload, secondary to enhanced ventricular interaction.

Background— Exercise intolerance is a hallmark of heart failure, but factors associated with impaired exercise capacity in heart failure with preserved ejection fraction are unclear. We hypothesized that in heart failure with preserved ejection fraction, the severity of resting ventricular and vascular dysfunction are associated with impairment in exercise tolerance as assessed by peak oxygen consumption. Methods and Results— Subjects with heart failure with preserved ejection fraction enrolled in the PhosphodiesteRasE-5 Inhibition to Improve CLinical Status And EXercise Capacity in Diastolic Heart Failure (RELAX) clinical trial (n=216) underwent baseline Doppler echocardiography, cardiopulmonary exercise testing, and cardiac MRI. RELAX participants were elderly (median age 69 years) and 48% were women. Ejection fraction (60%) and stroke volume (77 mL) were normal, while diastolic dysfunction (medial E / e ′, 16; deceleration time, 185 ms; left atrial volume, 44 mL/m 2 ) and increased arterial load (arterial elastance, 1.51 mm Hg/mL) were evident. Peak oxygen consumption was reduced (11.7 mLkg −1 min −1 , 1141 mL/min) and age, sex, body mass index, hemoglobin, and chronotropic response collectively explained 64% of the variance in raw peak oxygen consumption (mL/min). After adjustment for these variables, left ventricular structure (diastolic dimension [1.5%, P =0.008] and left ventricular mass [1.6%, P =0.008]), resting stroke volume (2.0%, P =0.002), left ventricular diastolic dysfunction (deceleration time [0.9%, P =0.03] and E / e ′ [1.4%, P =0.009]), and arterial function (arterial elastance [2.1%, P =0.002] and systemic arterial compliance [1.5%, P =0.007]), each explained only a small additional portion of the variance in peak oxygen consumption. Conclusions— In heart failure with preserved ejection fraction, potentially modifiable factors (obesity, anemia, and chronotropic incompetence) are strongly associated with exercise capacity, whereas resting measures of ventricular and vascular structure and function are not. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00763867

Background Medication treatment decisions in heart failure ( HF ) are currently informed by measurements of brachial artery pressure, but ventricular afterload is more accurately represented by central aortic pressure, which differs from brachial pressure. We sought to determine whether aggressive titration of vasoactive medicines beyond goal‐directed heart failure medical therapy ( GDMT ) based upon aortic pressure improves exercise capacity and cardiovascular structure‐function. Methods and Results Subjects with chronic HF (n=50) underwent cardiopulmonary exercise testing, echocardiography, and arterial tonometry to measure aortic pressure and augmentation index, and were then randomized to aortic pressure‐guided treatment (active, n=23) or conventional therapy (control, n=27). Subjects returned for 6 monthly visits wherein GDMT was first optimized. Additional vasoactive therapies were then sequentially added with the goal to reduce aortic augmentation index to 0% (active) or if brachial pressure remained elevated (control). Subjects randomized to active treatment experienced greater improvement in peak oxygen consumption compared with controls (1.37±3.76 versus −0.65±2.21 mL min −1 kg −1 , P =0.025) though reductions in aortic augmentation index were similar (−7±9% versus −5±6%, P =0.46). Forward stroke volume increased while arterial elastance and left ventricular volumes decreased in all participants, with no between‐group difference. Subjects randomized to active treatment were more likely to receive additional vasoactive therapies including nitrates, aldosterone antagonists and hydralazine, with no increased risk of hypotension or worsening renal function. Conclusions Maximization of goal‐directed medical therapy in heart failure patients may enhance afterload reduction and lead to reverse remodeling, while additional medicine titration based upon aortic pressure data improves exercise capacity in patients with heart failure.

ObjectivesWe set to measure the interatrial pressure gradient during simulated obstructive sleep apnea (OSA).BackgroundOSA occurs when a sleeping patient attempts to inhale against an obstructed airway. How this event affects the interatrial pressure gradient has not been defined. We hypothesized that simulated OSA in a conscious subject (Mueller maneuver [MM], inspiration against obstruction) would promote increased right‐to‐left pressure gradient, and then the substrate for right‐to‐left atrial shunting.MethodsSelected patients underwent simultaneous measurement of airway and atrial pressures (both left and right atrium [LA, RA]) using high‐fidelity micromanometry at rest, during MM, and during VM, during right heart catheterization.ResultsTen patients (age 55 ± 11 years, two women) were successfully studied. During the onset of MM, RA pressure transiently but consistently exceeded LA pressure in response to the steep decline in intrathoracic pressure (maximum RA‐LA pressure gradient increased from 0.1 ± 1.4 mm Hg at baseline to 7.0 ± 4.3 mm Hg during MM, P < 0.001). The maximum right‐to‐left atrial pressure gradient during Mueller maneuver was higher than that achieved during the Valsalva maneuver release (P < 0.007).ConclusionsThe onset of MM increased right‐to‐left pressure gradient across the atrial septum, likely as a result of greater blood return to the RA from extrathoracic veins. The RA‐LA pressure gradient achieved during MM was greater than that observed during VM. These findings delineate the hemodynamic substrate for right to left shunting during OSA. © 2014 Wiley Periodicals, Inc.