Author + information
- Received November 19, 2018
- Revision received January 10, 2019
- Accepted January 14, 2019
- Published online February 25, 2019.
- Anna L. Beale, MBBS, BMedScia,b,c,
- Shane Nanayakkara, MBBSa,b,c,
- Louise Segana,b,
- Justin A. Mariani, MBBS, PhDa,b,c,
- Micha T. Maeder, MD, PhDd,
- Vanessa van Empel, MD, PhDe,
- Donna Vizi, RNa,
- Shona Evans, NZSca,
- Carolyn S.P. Lam, MBBS, PhDf and
- David M. Kaye, MBBS, PhDa,b,c,∗ ()
- aDepartment of Cardiology, Alfred Hospital, Melbourne, Victoria, Australia
- bHeart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- cDepartment of Medicine, Monash University, Clayton, Victoria, Australia
- dCardiology Department, Kantonsspital St. Gallen, St. Gallen, Switzerland
- eDepartment of Cardiology, Maastricht University Medical Centre, Maastricht, the Netherlands
- fDepartment of Cardiology, National Heart Centre, Duke University, National University of Singapore Medical School, Singapore
- ↵∗Address for correspondence:
Prof. David M. Kaye, Department of Cardiology, Alfred Hospital, Commercial Road, Melbourne, Victoria 3004, Australia.
Objectives This study sought to identify sex differences in central and peripheral factors that contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF) by using complementary invasive hemodynamic and echocardiographic approaches.
Background Women are overrepresented among patients with HFpEF, and there are established sex differences in myocardial structure and function. Exercise intolerance is a fundamental feature of HFpEF; however, sex differences in the physiological determinants of exercise capacity in HFpEF are yet to be established.
Methods Patients with exertional intolerance with confirmed HFpEF were included in this study. Evaluation of the subjects included resting and exercise hemodynamics, echocardiography, and mixed venous blood gas sampling.
Results A total of 161 subjects included 114 females (71%). Compared to males, females had a higher pulmonary capillary wedge pressure (PCWP) indexed to peak exercise workload (0.8 [0.5 to 1.2] mm Hg/W vs. 0.6 [0.4 to 1] mm Hg/W, respectively; p = 0.001) and lower systemic (1.1 [0.9 to 1.5] ml/mm Hg vs. 1 [0.7 to 1.2] ml/mm Hg, respectively; p = 0.019) and pulmonary (2.9 [2.2 to 4.2] ml/mm Hg vs. 2.4 [1.9 to 3] ml/mm Hg, respectively; p = 0.032) arterial compliance at exercise. Mixed venous blood gas analysis demonstrated a greater rise in lactate indexed to peak workload (0.05 [0.04 to 0.09] mmol/l/W vs. 0.04 [0.03 to 0.06] mmol/l/W, respectively; p = 0.007) in women compared to men. Women had higher mitral inflow velocity to diastolic mitral annular velocity at early filling (E/e′) ratios at rest and peak exercise, along with a higher ejection fraction and smaller ventricular dimensions.
Conclusions Women with HFpEF demonstrate poorer diastolic reserve with higher echocardiographic and invasive measurements of left ventricular filling pressures at exercise, accompanied by lower systemic and pulmonary arterial compliance and poorer peripheral oxygen kinetics.
Consistent epidemiological data demonstrate that a greater proportion of women than men have heart failure with preserved ejection fraction (HFpEF) (1). Although this may be partially explained by sex differences in the distribution of the aging population and comorbidity density (2), there are also fundamental underlying sex differences in myocardial structure and function (3). Women have smaller ventricular chambers and poorer diastolic function (4); greater arterial elastance and wave reflection with aging (5); and a higher prevalence of coronary microvascular dysfunction that is closely linked to HFpEF than age-matched men (6,7).
Exercise intolerance is central to HFpEF, and the use of detailed exercise testing for the diagnosis of HFpEF is rapidly gaining acceptance as the preferred method (8). Invasive hemodynamic studies performed during exercise provide a sensitive approach to evaluation of diastolic reserve, facilitating HFpEF diagnosis and risk stratification (9,10). Moreover, a combined approach incorporating invasive hemodynamics, echocardiography, and analysis of mixed venous blood gases facilitates identification of abnormalities in different components in the oxygen consumption pathway (11). This multimodal approach enables an improved understanding of the factors contributing to exercise intolerance, such as impaired relaxation, reduced cardiac output, and impaired peripheral oxygen extraction.
Several studies have used invasive hemodynamics to identify subgroups of HFpEF patients in regard to potential mechanisms of exercise intolerance, differentiating on the basis of factors such as age (12), obesity (13), and pulmonary vascular disease (14). Sex differences in invasive exercise hemodynamics, however, have not been examined in patients with HFpEF. Thus, the present study sought to characterize sex differences in regard to invasive hemodynamics, structural parameters, and peripheral oxygen kinetics to better understand the key determinants of exercise limitations in women with HFpEF.
The study cohort included patients undergoing clinically indicated exercise right heart catheterization (RHC) together with those participating in research studies at the Alfred Hospital, Melbourne Australia during the period May 2008 to September 2018. Clinically indicated exercise RHC was usually in the setting of inconclusive noninvasive investigations.
Patients with symptoms consistent with a diagnosis of HF were defined as having HFpEF if they had an EF of ≥50% together with a resting pulmonary capillary wedge pressure (PCWP) ≥15 mm Hg or an exercise PCWP ≥25 mm Hg, in accordance with established definitions (15). Natriuretic peptide levels or echocardiographic parameters were not considered as part of the diagnostic criteria. Exclusion criteria were as follows: more than mild valvular stenosis or regurgitation; evidence of significant pulmonary disease on lung function testing or pulmonary imaging; chronic pulmonary emboli; hypertrophic cardiomyopathy; or previous heart transplantation.
Right heart catheterization protocol
Exercise RHC was performed using supine cycle ergometry as previously reported by us (9). All measurements and exercises were performed in an unfasted state together with regular medications. A 7-F Swan-Ganz catheter was inserted through the brachial or internal jugular vein with the patient under local anesthesia. End-expiratory measurements were taken from the right atrium, right ventricle, pulmonary artery, and PCWP position. Wedge position was confirmed by identification of the appropriate pressure waveform and by biochemical demonstration of an arterialized PCWP blood gas sample when required. Cardiac output was calculated using thermodilution, and the average of 3 measurements taken. Measurements recorded noninvasively included heart rate, systemic blood pressure, and arterial oxygen saturation by pulse oximetry. Noninvasive and invasive measurements were taken at rest at 3-min intervals during exercise until the patient reached their peak tolerated workload. An important feature of this approach is the application of a weight-corrected workload protocol, consisting of an initial workload of 0.3 W/kg with a rise to 0.6 W/kg every 3 min and to 1 W/kg after 12 min. Exercise duration was limited by patient symptoms (dyspnea or fatigue). Subjects were instructed to maintain a cycle cadence of 60 rpm during exercise.
Most patients had mixed venous blood gas measurements taken from the pulmonary artery at rest and at peak exercise. Resting and exercise lactate levels were measured in a subset of patients.
Transthoracic echocardiography was performed using a commercially available ultrasonography machine (model iE33, Phillips, Andover, Massachusetts) to obtain apical 2- and 4-chamber views, together with transmitral flow and tissue Doppler measurements. Approximately half of the cohort underwent resting echocardiography on the day of their exercise RHC (n = 73), a subset of which had exercise echocardiography simultaneous with their exercise RHC study immediately following peak exercise, performed by a single experienced echosonographer. The remainder of patients underwent transthoracic echocardiography within 112 (28 to 300) days of catheterization.
Invasive hemodynamic data are presented as raw values or indexed to body surface area (BSA) as appropriate. Given that the study focused on sex differences, the potential impact of differences in weight-related work capacity was accounted for by indexing key parameters to workload. In this context, the present authors and other investigators have reported workload-indexed PCWP in HFpEF (10). Similarly, the present authors reported metabolic parameters such as the mixed venous lactate concentration indexed to workload.
Pulmonary and systemic vascular compliance were calculated as the thermodilution-derived stroke volume-to-pulmonary and systemic arterial pulse pressure ratio, respectively (16). Arterial elastance (Ea) was calculated as: [0.9 × systemic systolic blood pressure/stroke volume] (17). End systolic elastance (Ees) was calculated as: [0.9 × systemic blood pressure/left ventricular end systolic volume]. End diastolic elastance (Ed) was calculated as [PCWP, used to estimate left ventricular Ed pressure/left ventricular Ed volume]. The Ea-to-Ees ratio was used to assess ventricular-vascular coupling (18). Rest and peak exercise oxygen consumption measurements were estimated as the difference between arterial and mixed venous oxygen content × cardiac output. Peripheral oxygen diffusion capacity (DMO2) was calculated as the oxygen consumption over the mixed venous partial pressure of oxygen (19).
Data are mean ± SD if normally distributed and median (interquartile range [IQR]) if nonparametric. The Student’s t-test was used for normally distributed data and the Wilcoxon signed-rank test for nonparametric data. Categorical variables were compared using the chi-square test for independence. A 2-tailed p value <0.05 was considered statistically significant. All statistical analyses were performed using R version 3.4.1 software (R Foundation for Statistical Computing, Vienna, Austria).
The study cohort consisted of 161 patients with HFpEF, of whom 114 (71%) were female. There were no significant differences between men and women with regard to age, body mass index, or B-type natriuretic peptide level. Men were more likely to have a history of ischemic heart disease; otherwise comorbidity rates did not differ between the sexes, as detailed in Table 1. A detailed medication history current with the RHC study was available in 97 patients and is reported in Table 1. Similar distributions across sexes were evident.
Echocardiographic data were recorded at rest in all patients (Online Table 1). Women had a higher EF at rest (62 ± 5% vs. 60 ± 7%, respectively; p = 0.018) and a higher mean mitral inflow velocity to diastolic mitral annular velocity at early filling (E/e′) ratio (10 [8 to 15] mm/s vs. 13 [10 to 17] mm/s, respectively; p = 0.037), despite similar left ventricular end diastolic diameters (46 ± 5 mm in women vs. 47 ± 5 mm in men; p = 0.084) and end systolic diameters (30 ± 5 mm vs. 31 ± 6 mm, respectively; p = 0.19). Left ventricular mass index was lower in women than in men (80 [71 to 99] g/m2 vs. 98 [77 to 114] g/m2; p = 0.018); however, the proportion of patients exceeding the gender-specific cutoff values for left ventricular hypertrophy (95 g/m2 for women; 115 g/m2 for men) did not differ between sexes. Left atrial volume index was similar between the sexes (40 [31 to 47] ml/m2 vs. 43 [35 to 53] ml/m2, respectively; p = 0.24). Pulmonary artery systolic pressure at rest did not differ between sexes (34 [17 to 63] mm Hg in women vs. 33 [21 to 85] mm Hg in men; p = 0.47). Tricuspid annular plane systolic excursion was greater in women (2.2 [1.9 to 2.8] cm) than in men (1.8 [1.7 to 1.8] cm; p = 0.037); however, when indexed to pulmonary artery systolic pressure to account for ventriculoarterial coupling (20), there were no differences between sexes.
Men and women achieved similar exercise durations (6 [3 to 7] min in men compared to 5 [3 to 8] min in women; p = 0.25). Peak exercise workload was significantly lower in women than in men (40 [25 to 60] W vs. 52 [31 to 70] W, respectively; p = 0.008). Resting heart rates (66 [60 to 76] beats/min in women vs. 67 [60 to 72] beats/min in men; p = 0.85) and exercise heart rates (98 [87 to 111] beats/min in women vs. 98 (83 to 110] beats/min in men; p = 0.54) did not differ between the sexes. Noninvasive blood pressure recordings revealed a significantly higher resting systolic blood pressure in women (150 [136 to 169] mm Hg vs. 141 [133 to 154] mm Hg, respectively; p = 0.037), along with a significantly higher exercise mean arterial pressure (121 ± 23 mm Hg vs. 113 ± 16 mm Hg, respectively; p = 0.04). Arterial pulse pressure at rest was higher in women at rest (76 [60 to 90] mm Hg) than that in men (64 [54 to 73] mm Hg; p = 0.002), and resting pulmonary arterial pulse pressure measurements were similar at rest across the sexes.
Invasive exercise hemodynamic data for all participants are shown in Table 2. Absolute arterial and pulmonary arterial pressures were similar in women, albeit at a lower workload. The raw PCWP with exercise (30 [27 to 33] mm Hg in men vs. 30 [27 to 34] mm Hg in women; p = 0.91) and rise in PCWP with exercise (16 [13 to 20] mm Hg in men vs. 17 [14 to 20] mm Hg in women; p = 0.47) prior to indexing to workload did not differ significantly between men and women. However, the rise in PCWP with exercise indexed to workload was significantly greater in women (Figure 1). Furthermore, women had a higher PCWP when indexed to stroke volume (Figure 1). The association between female sex and PCWP indexed to workload persisted after controlling for systolic blood pressure (p = 0.004). In the subgroup who underwent simultaneous echocardiography and catheterization (Table 3), women had higher E/e′ lateral values and mean E/e′ values at rest and markedly higher E/e′ lateral, septal, and mean values at exercise. Although e′ was lower in women at rest and at exercise, there were no differences in the delta septal e′ (2.1 [0.8 to 2.7] mm/s in men vs. 2 [1.1 to 2.8] mm/s in women; p = 0.9) nor in the delta lateral e′ (0.6 [0.1 to 1.9] mm/s in men vs. 1.8 [0.6 to 3] mm/s in women; p = 0.24).
Cardiac output was lower in women, both at rest (4.7 [4 to 5.6] l/mm) than in men (5.3 [4.7 to 6] l/min; p = 0.02) and at exercise (7.7 [6.6 to 9.6] l/min in women vs. 10 [7.1 to 11.7] l/min in men; p = 0.004); however, this was not different after indexing to BSA. Stroke volume indexed to BSA rose to a greater degree in men than in women (Figure 2). Women demonstrated significantly higher systemic and pulmonary vascular resistance levels (indexed to BSA) both at rest and during exercise, as shown in Table 4. Similarly, both systemic (Figure 3) and pulmonary compliance levels were lower in women at rest and exercise. Arterial elastance was significantly higher in women with exercise (2 [1.7 to 2.3] mm Hg/ml) versus that in men (1.5 [1.2 to 1.9] mm Hg/ml; p < 0.001), although this value did not retain statistical significance after indexing to BSA (3.5 [3 to 4] mm Hg/ml/m2 vs. 3.3 [2.7 to 3.9] mm Hg/ml/m2, respectively; p = 0.17). Indexed Ees was higher in women at rest and exercise, and similarly, Ed was higher in women at peak exercise. Ventricular vascular coupling, as represented by the Ea/Ees ratio, was lower in women after indexing to BSA at rest (1.02 [0.8 to 1.4]) than in men (1.2 [1 to 1.8]; p = 0.05) and after exercise (0.8 [0.8 to 1] vs. 0.7 [0.6 to 1], respectively; p = 0.09), although the latter did not reach statistical significance (Figure 3).
As shown in Table 5, mixed venous gases were obtained in 142 patients (88%), but a smaller proportion (56%) had available lactate levels. There were no significant sex differences between baseline or exercise mixed venous oxygen saturation, arteriovenous oxygen differences, oxygen consumption levels, or oxygen exchange ratios. DMO2 calculated at rest was significantly higher in men but at exercise did not differ between the sexes. The raw values of lactate at rest and exercise were similar in men and women. However, after indexing to workload, women had a significantly higher exercise lactate level (0.09 [0.07 to 0.13] mmol/l) than men (0.06 [0.05 to 0.08] mmol/l/W; p = 0.003), along with a higher rise in lactate level than in men.
The present study is the first to investigate, in detail, differences in the exercise hemodynamic profiles of men and women with HFpEF. Findings are particularly relevant given that some features of HFpEF may not be appreciated by testing under resting conditions. A complex pattern of physiologic changes were observed in women with HFpEF compared to that in men. Women had evidence of a greater degree of impairment of left ventricular diastolic reserve, which has been ascribed a central role in HFpEF pathophysiology. This was reflected by a greater rise in PCWP for a given workload and also by a greater rise in PCWP indexed to the exercise-mediated change in stroke volume. Women had a smaller rise in stroke volume index with exercise. Women also displayed relatively more advanced degrees of systemic and pulmonary vascular dysfunction as reflected by abnormalities in vascular resistance, compliance, and elastance. Finally, metabolic investigations showed a greater increase in mixed venous lactate when indexed to workload. Taken together, these data highlight a complete range of sex differences in central and peripheral limitations to functional capacity in HFpEF (Central Illustration).
The invasive hemodynamic findings of impaired left ventricular diastolic performance in women during exercise were also supported by echocardiographic findings, as reflected by a lower e′, higher E/e′ ratio, and higher Ed in women at exercise. Previous studies have suggested the presence of poorer diastolic function on resting echocardiography, reflecting greater ventricular stiffness in women (4,5,21,22). Furthermore, female sex is an independent predictor of abnormal exercise E/e′ ratios (23). The present hemodynamic findings are consistent with those from a previous study demonstrating a steeper rise in PCWP with rapid saline loading in healthy older women than in men, along with a steeper climb in mean pulmonary artery pressure in younger women than in age-matched men during saline loading (24). From a mechanistic perspective, previous experimental studies investigating the effect of sex on ventricular mechanics have shown greater increases in Ees with aging in women than those in men (5). Although increases in ventricular elastance are necessary to match arterial elastance and maintain mechanical efficiency, this occurs at the expense of diastolic function (5). A fall in the Ea/Ees ratio with exercise is attributable to greater relative increases in Ees than in Ea (25). This fall was observed in the Ea/Ees ratio at exercise to a greater extent in women, due to a greater rise in Ees, which may be due to increased arterial wave reflection in women (5,25).
Women had a similar stroke volume index (SVI) at rest; however, the exercise SVI was lower in women, and similarly, the rise in SVI with exercise was significantly attenuated in women. Women’s EF at exercise trended higher, consistent with established data highlighting a higher EF in women, particularly with aging (26). Thus, the blunted rise in SVI with exercise in women likely reflects the higher relative afterload in women with exercise, rather than impaired contractility, and may contribute to exercise intolerance in women. The higher Ees with exercise in women supports this inference.
There were sex differences in the systemic vasculature with lower systemic compliance at rest and at exercise, along with a trend toward higher arterial elastance and systemic vascular resistance at exercise in women with HFpEF than in men. This agrees with established evidence regarding increased arterial stiffening with aging in women compared to men (5). Furthermore, women are more sensitive to afterload-induced diastolic dysfunction than men (5,27), strengthening the relationship between higher arterial elastance and impaired diastolic reserve.
Another key contributor to the strong relationship between lower systemic compliance and greater PCWP indexed to workload in women may be small-caliber arterial function, which is poorer in women than in men. A study using flow-mediated dilation and peripheral arterial tonometry in the Framingham Heart Study (NCT00005121) cohort identified the fact that women are more likely to experience abnormal vascular function in the presence of comparable cardiovascular risk factors (28). Furthermore, women have a higher prevalence of coronary microvascular disease (29), which, beyond contributing to systemic vascular resistance, could directly cause myocardial hypertrophy and fibrosis, and affect the PCWP (6).
The present study demonstrated lower pulmonary arterial compliance in women at rest and exercise. This finding may be secondarily related to the chronic effects of higher left atrial pressure. Higher PCWP for any given pulmonary vascular resistance has been shown to cause greater pulmonary arterial wave reflection and lower pulmonary compliance (16). Alternatively, the sex differences in pulmonary arterial compliance with exercise may reflect intrinsic differences in pulmonary vascular reactivity. Although the underlying pathophysiology is not entirely clear, women have a far greater prevalence of idiopathic pulmonary arterial hypertension, affecting 4 times as many women as men (30). This may suggest that there are intrinsic sex differences in pulmonary vascular function and remodeling, contributing to exercise intolerance independent of PCWP.
Peripheral oxygen kinetics also differed between the sexes. Women were found to have significantly lower DMO2 at rest than men, a difference that was not seen at exercise. However, women did not augment their DMO2 with exercise to the same degree, although this did not reach statistical significance. This may suggest that our inability to find a difference in DMO2 at exercise could simply be due to insufficient participants. After indexing to workload, a marked rise in lactate levels were identified, along with a higher peak exercise lactate level in women. Lactate release is related to the ventilatory threshold in both healthy control subjects and heart failure patients (31), which corresponds to exercise capacity. This higher lactate level indexed to workload in women may be attributable to physical inactivity, given global data suggesting higher levels of inactivity in women than in men (32). Furthermore, lower DMO2 at rest, along with sharper rises in lactate with exercise, could relate to impairments in skeletal muscle and mitochondrial function, which are key cardiometabolic abnormalities in HFpEF (33). Muscle fiber types and capillary-to-fiber ratios (34) may also play a role in these observed sex differences in peripheral oxygen kinetics.
A higher PCWP indexed to workload, lower systemic and pulmonary compliance, higher ventricular elastance, and a greater rise in lactate indexed to workload was identified, suggestive of poorer peripheral oxygen use in women than in men. Interventions that target these defects to date have been variably effective. Mineralocorticoid receptor antagonists, although initially promising due to their actions on endothelial function, vascular inflammation, and fibrosis along with diuresis, have not been successful when examined in a large randomized trial (35). Similarly, trials of modulators of cardiomyocyte diastolic function, focusing on the nitric oxide and cyclic guanosine monophosphate pathways, have been largely ineffective to date, although studies are ongoing (33). Pulmonary vasodilator therapy has not proven effective as a therapy for HFpEF in randomized trials; however, there may be subgroups who derive more benefit, such as those with combined post-capillary pulmonary hypertension (33) and perhaps women with lower pulmonary compliance.
Randomized trials of exercise intervention in HFpEF have achieved augmented peak oxygen consumption, better exercise tolerance, and improved quality of life and echocardiographic parameters (36). Exercise training improves multiple components of the oxygen consumption pathway, particularly by boosting peripheral oxygen kinetics (37), including mitochondrial function. Exercise also induces functional and structural changes in large arteries and microvasculature alike. Increased systolic blood pressure and pulse pressure during periods of exercise stimulates the growth of endothelial cells and increases cyclic circumferential vascular strain, leading to downstream gene expression changes affecting endothelium-dependent vasodilator pathways including nitric oxide synthase. Additionally, cyclical smooth muscle cell stretch with exercise alters synthesis of factors affecting the vessel wall matrix. Thus, exercise training improves endothelial function, flow-mediated dilation, and vascular function (38), all centrally relevant to HFpEF, and may be of particular relevance to women in the context of their impairments in vascular compliance with exercise described in the present study. Mitigating elevated arterial elastance also relies on aggressive management of hypertension in women, particularly given the higher augmentation index seen in women (39) and aforementioned ventricular susceptibility to load-induced remodeling (27).
It was a retrospective study conducted over a 10-year period, involving patients recruited for both clinical and research indications. Therefore, the measurements taken differed slightly among patients recruited at different time points, such as lactate levels, exercise echocardiography, and clinical information, particularly medications. Not all patients had simultaneous echocardiography and RHC. Indices of arterial endothelial and small vessel function were unable to be measured, which, as mentioned, are important in the pathogenesis of HFpEF and differ between sexes. Furthermore, as a single-center study, the results might have been affected by selection and referral bias.
Women with HFpEF display a complex pattern of pathophysiologic differences compared to men. Women demonstrated more substantial features of impaired diastolic reserve, with a greater rise in PCWP for a given workload. This is associated with lower systemic and pulmonary compliance, suggestive of a concomitant vascular abnormality, potentially related to a longer duration of HFpEF and contributing factors such as hypertension. In addition, women had a greater rise in lactate indexed to workload, highlighting impairments at multiple stages of the oxygen consumption pathway. These findings highlight the importance of investigating the physiologic factors that contribute to symptoms and may suggest the application of differing treatment regimens. Further research should explore factors that distinguish HFpEF with extremely limited exercise duration compared to those in which a broader range of mechanisms may contribute.
COMPETENCY IN MEDICAL KNOWLEDGE: This study used invasive hemodynamics and simultaneous echocardiography and biochemistry at rest and at peak exercise in HFpEF patients to highlight more severe impairments in diastolic reserve in women than in men. This was demonstrated by a greater rise in PCWP indexed to workload, a greater E/e′ ratio, and higher Ees and Ea values accompanied by lower Ea/Ees ratio characteristic of poorer ventricular-vascular coupling, all of which are central to HFpEF. Furthermore, women had lower systemic and pulmonary compliance along with a greater rise in lactate levels for any given workload, indicative of impairments in multiple determinants of exercise tolerance.
TRANSLATIONAL OUTLOOK: These findings have important translational implications for studies of therapeutic agents in HFpEF, as therapies with specific mechanistic targets such as diastolic reserve or vascular compliance may be particularly effective in women. Further large randomized clinical trials should take sex into account as part of their trial design, to investigate their utility in women compared to that in men, particularly in modifying the aforementioned determinants of exercise tolerance.
Dr. Lam has received support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; and serves on the advisory boards of Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research and Development, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, and Darma. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- body surface area
- peripheral oxygen diffusion capacity
- arterial elastance
- end diastolic elastance
- end systolic elastance
- ejection fraction
- heart failure with preserved ejection fraction
- pulmonary capillary wedge pressure
- right heart catheterization
- Received November 19, 2018.
- Revision received January 10, 2019.
- Accepted January 14, 2019.
- 2019 American College of Cardiology Foundation
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