Author + information
- Received June 3, 2019
- Revision received August 22, 2019
- Accepted August 26, 2019
- Published online November 18, 2019.
- Masaru Obokata, MD, PhDa,
- Yogesh N.V. Reddy, MBBS, MSca,
- Sanjiv J. Shah, MDb,
- David M. Kaye, MD, PhDc,
- Finn Gustafsson, MD, PhDd,
- Gerd Hasenfuβ, MDe,
- Elke Hoendermis, MD, PhDf,
- Sheldon E. Litwin, MDg,
- Jan Komtebedde, DVMh,
- Carolyn Lam, MBBS, PhDf,i,j,
- Daniel Burkhoff, MD, PhDk and
- Barry A. Borlaug, MDa,∗ (, )@bborlaugmd@mayoclinicCV
- aDepartment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
- bDivision of Cardiology, Northwestern University, Chicago, Illinois
- cBaker IDI Heart and Diabetes Institute and Alfred Hospital, Melbourne, Victoria, Australia
- dDepartment of Cardiology, Rigshospitalet, Copenhagen, Denmark
- eGeorg-August Universität, Heart Centre, Gottingen, Germany
- fUniversity Medical Center Groningen, Groningen, the Netherlands
- gMedical University of South Carolina, Charleston, South Carolina
- hCorvia Medical, Tewksbury, Massachusetts
- iNational Heart Centre Singapore and Duke-National University of Singapore, Singapore
- jThe George Institute for Global Health, Newtown, New South Wales, Australia
- kDivision of Cardiology, Columbia University, New York, New York
- ↵∗Address for correspondence:
Dr. Barry A. Borlaug, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905.
Background Implantation of an interatrial shunt device (IASD) in patients with heart failure (HF) reduces left atrial hypertension by shunting oxygenated blood to the right heart and lungs. The attendant increases in pulmonary blood flow (Qp) and oxygen content may alter pulmonary vascular function, while left-to-right shunting might compromise systemic perfusion.
Objectives The authors hypothesized that IASD would improve indexes of pulmonary artery (PA) function at rest and during exercise in HF patients without reducing systemic blood flow (Qs).
Methods This is a pooled analysis from 2 trials assessing the effects of the IASD on resting and exercise hemodynamics in HF patients (n = 79) with EF ≥40% with baseline and repeated hemodynamic evaluation between 1 and 6 months. Patients with pulmonary vascular resistance (PVR) >4 WU or right ventricular dysfunction were excluded.
Results Qp and PA oxygen content increased by 27% and 7% following IASD. These changes were associated with salutary effects on pulmonary vascular function (17% reduction in PVR, 12% reduction in PA elastance [pulmonary Ea], and 24% increase in PA compliance). Qp increased during exercise to a greater extent following IASD compared with baseline, which was associated with reductions in exercise PVR and pulmonary Ea. Patients with increases in PA compliance following IASD experienced greater improvements in supine exercise duration. There was no reduction in Qs following IASD at rest or during exercise.
Conclusions Implantation of an IASD improves pulmonary vascular function at rest and during exercise in selected patients with HF and EF ≥40%, without compromising systemic perfusion. Further study is warranted to identify underlying mechanisms and long-term pulmonary hemodynamic effects of IASD. (REDUCE LAP-HF Trial [REDUCE LAP-HF]; NCT01913613; and REDUCE LAP-HF Randomized Trial I [REDUCE LAP-HF I]; NCT02600234)
Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence, and there are limited treatments (1). Left atrial (LA) hypertension develops during exercise in people with HFpEF, leading to dyspnea, pulmonary hypertension, lung congestion, impairments in exercise capacity, and increased mortality (2–6). A novel transcatheter interatrial shunt device (IASD) (Corvia Medical, Tewkesbury, Massachusetts) has been developed as an investigational treatment for HF. The IASD creates a small (8-mm diameter) left-to-right shunt, enabling LA decompression when LA pressures rise. This is associated with a reduction in pulmonary capillary pressures during exercise (7–13).
In addition to LA decompression, this intervention may alter cardiovascular homeostasis in other ways relevant to the pathophysiology of HFpEF. Implantation of the IASD causes an increase in pulmonary blood flow (Qp), while also increasing the oxygen (O2) tension in the mixed venous blood delivered to the lungs. Both of these may influence the function or structure of the pulmonary vasculature, potentially through effects on hypoxic vasoconstriction, vascular and capillary recruitment, and flow-mediated dilation. Conversely, a newly created left-to-right shunt could reduce systemic blood flow (Qs), impairing convective delivery of O2 to the tissues, which is often compromised in patients with HFpEF (4,14,15).
We hypothesized that the increase in lung perfusion with more richly oxygenated blood following IASD would have beneficial effects on pulmonary vascular function at rest and during exercise, without compromising systemic O2 delivery. To test this hypothesis, we performed a pooled analysis to determine the effects of the IASD on pulmonary hemodynamics at rest and during exercise in patients with HF and EF ≥40%.
Study design and participants
This analysis used data from subjects participating in the REDUCE LAP-HF (A Study to Evaluate the DC Devices, Inc. IASD System II to REDUCE Elevated Left Atrial Pressure in Patients With Heart Failure) (NCT01913613) and REDUCE LAP-HF I (NCT02600234) trials designed to assess the performance and safety of a transcatheter IASD (Corvia Medical) in patients with HF and EF ≥40%. Patients were recruited from participating institutes in the United States, Europe, Australia, and New Zealand. The study designs and primary results have been published (7–13). Briefly, REDUCE LAP-HF was a multicenter, nonrandomized, open-label, single-arm, phase 1 trial that enrolled patients with HFpEF at 21 centers in Europe, Australia, and New Zealand between February 2014 and June 2015 (8–10). Patients were eligible if they had evidence of chronic symptomatic HF, an LVEF >40%, and an increased pulmonary capillary wedge pressure (PCWP) at rest (>15 mm Hg) or during exercise (>25 mm Hg). The implantation of the IASD was successful in 64 patients. There was 1 device-related adverse event. This was a device malposition without clinical sequelae. The device was retrieved percutaneously removal, and a second IASD was inserted, resulting in a successful implant. Of the 64 participants, 60 patients underwent second right heart catheterization at 6 months. REDUCE LAP-HF I was a multicenter, prospective, phase 2, randomized, blinded controlled trial with nonimplant (sham) control group and 1-to-1 randomization (11–13). Key inclusion criteria were symptomatic HF, an LVEF ≥40%, elevated end-expiratory PCWP during supine exercise (≥25 mm Hg), and PCWP-right atrial (RA) pressure gradient ≥5 mm Hg. Patients with significant pulmonary vascular disease (pulmonary vascular resistance [PVR] >4 WU) or right ventricular (RV) dysfunction were excluded in both trials. A total of 44 patients (the IASD arm, n = 22) were randomized at 22 centers in the United States, Europe, and Australia between February 2016 and November 2016. One patient withdrew from the study at the time of the index procedure because of an inability to access the right atrium for insertion of the intracardiac echocardiography probe. Of the 21 remaining participants in whom implantation was attempted, there was 1 patient in whom the IASD device was fully deployed in the LA instead of the interatrial septum, the device was percutaneously retrieved, and implantation of a second IASD was not attempted. Of the 20 participants who underwent successful device implantation, 1 refused repeat right heart catheterization at 1 month. None of the IASD-treated participants (n = 21) experienced device-related perioperative adverse events through 1 month of follow-up. At 12 months of follow-up, 1 major adverse cardiac event occurred in the IASD group.
For the current study, patients who had successfully received the treatment and completed repeated right heart catheterization were included for the analysis (n = 79) (Figure 1). All patients underwent 2-dimensional, Doppler, and tissue-Doppler echocardiography according to independent core laboratory standards at baseline visit. LV systolic and diastolic function, RV size and function, valvular heart disease, and interatrial flow through the device were evaluated. Submaximal exercise capacity was assessed using the 6-min walk distance in a subset of participants (n = 79 at baseline and n = 60 at follow-up). Quality of life (QOL) was assessed by 2 different instruments: the Minnesota Living with Heart Failure score in the open-label REDUCE LAP-HF trial (score range 0-105, lower scores indicate better QOL) and the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the randomized REDUCE LAP-HF I trials (score range 1 to 100, higher scores indicate better QOL). The study protocol was approved by the institutional review board or ethics committee at each institution. All patients provided written informed consent.
All patients underwent right heart catheterization in the supine position both at baseline and follow-up after device implantation (6 months in the open-label study [REDUCE LAP-HF] and 1 month in the randomized controlled trial [REDUCE LAP-HF I]) (8,13). Right atrial, PCWP, and pulmonary artery (PA) pressures were measured using a fluid-filled balloon-tipped catheter. The driving force for flow through the IASD was estimated from the pressure gradient between the PCWP and RA pressure (16). Pulmonary blood flow (Qp) was measured as right-sided cardiac output (CO) using the thermodilution method. Intraindividual variability of CO measurements were evaluated in a subset of participants (n = 60): 0.36 ± 0.22 l/min at rest and 0.59 ± 0.54 l/min during exercise; coefficients of variance, 6.7 ± 3.9% at rest and 6.8 ± 5.4% during exercise. Pulmonary vascular resistance ([mean PAP − PCWP]/Qp), PA compliance (PAC = PA stroke volume [SV]/pulmonary pulse pressure), and PA elastance (pulmonary Ea = PA systolic pressure/PA SV) were calculated.
Oxyhemoglobin saturations were measured in blood samples taken from the superior and inferior vena cava, the PA, and the systemic arterial circulation at rest to determine the magnitude of left-to-right shunting as indexed by the pulmonary-to-systemic blood flow ratio (Qp/Qs), both before and following IASD. For the initial assessment (with septum intact), exercise Qp/Qs was assumed to be equivalent to values at rest. Mixed venous O2 saturation during exercise following IASD (i.e., upstream of the “step up” in O2 saturation related to the IASD) was assumed to be same as that measured at baseline with septum intact. Systemic blood flow (Qs) was then calculated from directly measured Qp and the measured Qp/Qs ratio.
Pulmonary artery and systemic O2 contents were determined by the saturation and hemoglobin (saturation × hemoglobin × 1.34 × 10). Systemic O2 delivery in ml/min was then calculated as the product of Qs and systemic O2 content. Right and left ventricular stroke work was calculated: ([mean PAP − RAP] × PA SV × 0.0136) and ([mean arterial blood pressure − PCWP] × SV × 0.0136) (17). Following resting measurements, patients exercised using a supine cycle ergometer, starting at 20 W workload and increasing in 20-W increments (3 min/stage) until subject-reported exhaustion. Central hemodynamics and Qp were again acquired at peak exercise using the same methods. The hemodynamic assessment protocol was identical at all study centers and between the 2 trials.
Device implantation was performed percutaneously via the femoral vein as previously described (9,11,12). Briefly, transseptal puncture of the interatrial septum and IASD implantation were performed with guidance of fluoroscopy and transesophageal or intracardiac echocardiography. The IASD has an internal diameter of 8 mm.
Data are reported as mean ± SD, median (interquartile range), or number (%). Differences between baseline and follow-up visit were compared using the paired Student’s t-test or Wilcoxon signed rank test among patients with paired measurements, as appropriate. Given the low prevalence of missing data in the current analysis, values at baseline and follow-up are presented for all patients who could be measured at each point. Pearson’s or Spearman’s correlation were used to evaluate the correlations between 2 variables. All statistical tests were 2-sided, and a p value <0.05 was considered statistically significant. All of the statistical analyses were performed using JMP Pro statistical software version 14.0 (SAS Institute, Cary, North Carolina).
A total of 79 subjects were included (Figure 1). At baseline, participants were elderly, obese, highly symptomatic (80% New York Heart Association functional class III) and displayed multiple comorbidities including hypertension, diabetes, and history of any atrial fibrillation (AF) (Table 1). Of the 32 patients with history of AF, 14 (44%) had current AF at baseline evaluation. On echocardiography, mean core laboratory–assessed LVEF was 47%, and 32% of participants had EF ≥50%. Right ventricular size and function were within the normal range. Subjects displayed impaired LV diastolic function, evidenced by elevated E/eʹ ratio (Table 1).
Compared with the open-label REDUCE LAP-HF (n = 60), participants from the randomized REDUCE LAP-HF I trial (n = 19) were more likely to be men and had higher prevalence of New York Heart Association functional class III and lower hemoglobin and estimated glomerular filtration rate levels, but there were no other relevant differences in baseline characteristics or echocardiographic indexes (Online Table 1).
Baseline hemodynamics at rest and during exercise with septum intact
As expected, the Qp/Qs ratio at baseline prior to IASD was near unity in keeping with the absence of an existing shunt, as specified by eligibility criteria (Table 2). Left and right heart filling pressures and mean PA pressure were elevated at rest compared with expected normal ranges and became even more markedly elevated with exercise (Tables 2 to 3). Peak exercise workload was depressed compared with expected normal levels (43 ± 18 W). Similar to prior studies (4,17), patients displayed impaired pulmonary vasodilation during exercise, manifest by blunted reductions in PVR and pulmonary Ea and marked reduction in PAC (Tables 2 and 3).
Effect of IASD implantation on resting hemodynamics
Shunt patency was documented in 78 of 79 patients at 6 months (follow-up echocardiogram was not obtained in the other participant). At follow-up, the Minnesota Living With Heart Failure score was improved from 49 ± 20 to 36 ± 23 in the open-label trial (n = 60; p < 0.0001), the overall KCCQ score tended to improve in the randomized trial (n = 19, 44 ± 19 to 53 ± 20; p = 0.10), and 6-min walk distance was increased from 328 ± 89 m to 356 ± 99 m (p = 0.004) in a subset of paired data (n = 60). Following IASD implantation, there were significant decreases in PCWP and the PCWP-RAP gradient, and an increase in RA pressure, consistent with creation of a small left to right shunt (Table 2). Pulmonary blood flow increased by 27%, the Qp/Qs ratio increased to 1.23 ± 0.27, and PA O2 saturation and content increased, with a rightward shift in the PA pressure-flow relationship (Table 2, Figures 2A and 2B). These changes were associated with favorable effects on pulmonary vascular tone, evidenced by a 17% reduction in PVR, 12% reduction in pulmonary Ea, and 24% increase in PAC (Figure 2A). Improvements in pulmonary vascular function directly correlated with the magnitude of change in Qp following IASD (Figure 3). Patients with higher PA O2 content following IASD displayed lower PVR (r = −0.24; p = 0.04). Placement of the IASD was associated with increases in RV and LV stroke work, but did not decrease Qs or systemic O2 delivery at rest. Results were similar when analyzing the 2 trial cohorts separately (Online Tables 2 and 3).
Effect of IASD implantation on exercise hemodynamics
Implantation of the IASD was associated with a 14% increase in supine exercise duration (7.4 ± 3.0 min to 8.4 ± 3.8 min; p = 0.006) and 12% increase in peak workload achieved (43 ± 18 W to 48 ± 20 W; p = 0.003). Exercise PCWP and the PCWP to RA pressure gradient were both decreased after device implantation, and patients were able to exercise to a higher peak heart rate (Table 3).
Compared with the baseline exercise study with septum intact, Qp was 25% higher during exercise following IASD, and the net increase in Qp during exercise was greater (Figure 4). Despite the presence of left to right shunt, Qs and systemic O2 delivery during exercise tended to be increased compared with baseline evaluation with septum intact (Table 3, Figure 4). Similar to pulmonary vascular effects at rest, PAC was higher and pulmonary Ea lower during exercise following IASD.
The increase in PCWP relative to Qp was significantly reduced following IASD (Table 3). Because patients with greater ability to enhance PA compliance might be expected to respond more favorably to the increase in Qp associated with IASD, we conducted an exploratory analysis comparing exercise responses in patients with and without an increase in PAC. This revealed that participants with an increase in PAC following IASD (n = 49) displayed greater improvements in supine exercise duration compared with participants in whom PAC failed to increase (n = 23) (Figure 4). As with rest effects, exercise hemodynamic effects were generally similar when evaluating the individual trials separately rather than the main combined analysis (Online Tables 2 and 3).
Impact of AF
Given the high prevalence of AF and its impact on both LA and pulmonary vascular function in HFpEF (18), we performed a subgroup analysis to evaluate whether the observed effects of IASD on pulmonary hemodynamics differed between patients with and without baseline history of any AF. Compared with patients without AF (n = 47), those with baseline AF (n = 32) were older (72 ± 6 years vs. 68 ± 8 years; p = 0.03) more likely to be men (59% vs. 28%; p = 0.005), and displayed worse hemodynamics at rest and during exercise at the baseline visit (Online Table 4). Following IASD implantation, there was greater increase in resting Qp in patients with AF than those without (37% vs. 20%; p = 0.001) that was associated with greater reductions in PVR and pulmonary Ea (PVR, −30% vs. −2%; p = 0.003; pulmonary Ea, −23% vs. −5%; p = 0.01). Changes in resting PCWP, PA saturation, and systemic flow and O2 delivery following IASD were similar between the groups (all p > 0.10).
This study provides a comprehensive evaluation of the effects of the IASD on resting and exercise pulmonary hemodynamics in patients with HF from the REDUCE LAP-HF (open-label) and REDUCE LAP-HF I (randomized) trials. The novel finding of this study is that increases in Qp and PA O2 content following IASD are associated with salutary effects on pulmonary vascular function, with improvements in PVR, PAC, and pulmonary Ea. Compared with baseline, Qp increased during exercise to a greater extent following IASD, which was coupled with favorable reductions in pulmonary Ea and improvement in PA compliance during exercise. These beneficial effects of IASD were not accompanied with reductions in systemic blood flow or systemic O2 delivery, either at rest or with exercise stress. Patients with greater PA compliance reserve experienced greater improvements in exercise capacity. Collectively, these data indicate that on average, up to 6 months following IASD implantation, the lungs are able to accommodate the increase in blood flow associated with the IASD in HF patients with EF ≥40% (and without significant pulmonary vascular disease or RV dysfunction at baseline), and that these increases in blood flow and O2 content are associated with favorable effects on pulmonary vascular function, potentially mitigating risk for progression in pulmonary vascular disease, without compromising systemic perfusion, which could worsen peripheral O2 delivery during stress.
Pulmonary vascular disease in HFpEF
This analysis confirms and expands upon the previously published findings, showing a significant reduction in left-sided filling pressure during exercise after IASD implantation (7–13). However, recent studies have shown that left atrial hypertension is not the only important pathophysiological target in HFpEF, as pulmonary vascular disease is also common. Patients with HFpEF and pulmonary vascular disease display worse hemodynamics, impaired RV reserve, reduced exercise capacity, and poorer clinical outcomes when compared with HFpEF patients with isolated left heart disease (17,19–23). One potential effect of a shunt could be an impairment in pulmonary structure or function. In patients with large, uncorrected left to right shunts, increases in Qp lead to vascular remodeling, elevation in PVR, and RV failure, the so-called Eisenmenger syndrome (24). While Eisenmenger physiology takes years to develop, and is uncommon in patients with an “isolated” ASD, the potential for worsening pulmonary vascular disease in a patient with HFpEF is a possibility. Conversely, the structural and functional abnormalities that develop in the pulmonary vasculature in HFpEF are most fundamentally related to LA hypertension (21), which is favorably reduced by IASD (7–13). Indeed, a recent study observed that elevation in PCWP, which is directly targeted by the IASD, was one of the strongest predictors for developing incident RV dysfunction (18).
Effects of IASD on pulmonary vascular function
The current study demonstrates that there are improvements in pulmonary vascular function after the implantation of the IASD, manifest by lower PVR and pulmonary Ea, and improvement in PAC, which are sustained out to 6 months of follow-up. Although the precise mechanisms underlying these hemodynamic effects cannot be determined from this study, there are 3 key possibilities that are most likely: flow-dependent vasodilatory effects related to the IASD, pulmonary vasodilation due to improved PA O2 content from the mixing of oxygenated shunt blood flow, and reduction in pulmonary arterial pulsatile load due to the LA unloading (Central Illustration).
Improvements in resting pulmonary vascular function after the IASD implantation was associated with the magnitude of increase in Qp (Figure 3). This may be related to enhanced recruitment and distention of underperfused zones of the pulmonary circulation (25,26). In the isolated canine lung at constant mean PA pressure, LA pressure, and airway pressure, augmentation in Qp increases the number of recruited capillaries while decreasing PVR (26,27). The distention of the pulmonary vasculature also increases vascular conductance, which may lead to further reduction in the resistance (28). In keeping with these mechanisms, in an animal model of HFpEF, creation of an interatrial shunt was recently shown to increase PA wall shear rate and lead to an increase in pulmonary vascular endothelial nitric oxide synthase protein expression, which may contribute to the observed improvements in pulmonary vascular function (29).
Elevation in PVR in HFpEF has been shown to be associated with venous hypoxia (4), which promotes vasoconstriction in precapillary PH (30). Increases in mixed venous O2 content secondary to the left to right shunt observed in this study following IASD may therefore promote pulmonary vasodilation. In support of this mechanism, surgical correction of left-to-right shunt leads to paradoxical reduction in PAC (31). Hypoxic vasoconstriction may be particularly problematic during exercise in HFpEF, where mixed venous O2 content falls dramatically due to enhanced tissue extraction in the setting of reduced Qs (4,14), with the potential for worsening PH and RV-PA uncoupling (17). In addition to IASD, other means of augmenting PA O2 content using O2 enriched air or through treatment of iron deficiency may also improve pulmonary vascular function and merit future study (32–34).
An increase in left-sided filling pressure may increase wave reflections and worsens PA compliance, increasing pulsatile RV afterload (35,36). We observed that among the indexes of pulmonary vascular function, PAC improved the most. This is likely related to the fact that PA compliance and resistance share a hyperbolic relationship, meaning that in the range of relatively low PVR (as in the current sample), there are relatively greater changes in PAC with pulmonary vascular effects. Furthermore, the reduction in PCWP likely further contributed to the increase in PAC, in agreement with earlier studies (35). PA compliance is related to the ability of the pulmonary vasculature to accept the stroke volume ejected by the RV without excessive swings in pressure. The fact that PAC improved on average indicates that these HF patients (where more dramatic PH was excluded by design) do in fact have compliance reserve. Importantly, the patients that were better able to recruit this PAC reserve enjoyed the greatest beneficial effects of IASD on exercise capacity (Figure 4), emphasizing the importance of pulmonary vascular function in the pathophysiology of exercise intolerance across the spectrum of HFpEF (17). However, patients with more significant pulmonary vascular disease or RV dysfunction at baseline were excluded from these trials, and these results may not apply to this cohort of patients. Further study is needed to identify patients with greater pulmonary compliance reserve who may drive greater benefit from IASD.
The IASD and systemic O2 delivery
Cardiac output reserve is impaired in patients with HFpEF and associated with reduced aerobic capacity (4,14). Systemic O2 delivery is the product of Qs and arterial O2 content, and in computer simulations, IASD implantation is associated with a 10% to 15% reduction in Qs, which, if present, would be expected to compromise exercise capacity and potentially mitigate the beneficial effects related to LA decompression (7). However, that simulation did not account for autonomic reflexes that serve to rapidly regulate systemic blood pressure and flow. In fact, as previously reported, we observed that both Qs and systemic O2 delivery did not decrease following IASD implantation, either at rest or (as estimated) during exercise, but in fact tended to increase. Qs is known to increase in tandem with increases in metabolic demand (VO2) during exercise in a tightly regulated manner, although the mediators underlying this regulation are unknown (37). The current data show that systemic perfusion is well-maintained following IASD, coupled with improvements in biventricular performance as evidenced by increases in RV and LV stroke work.
Impact of atrial fibrillation
Atrial fibrillation is associated with LA remodeling and dysfunction, pulmonary hypertension, and RV dysfunction in patients with HFpEF (18,38). Thus, the presence of AF could be associated with a more adverse response to IASD given the potential stress on the RV-PA circuit due to the increase in Qp. However, we observed greater reduction in resting PVR and pulmonary Ea following IASD implantation in patients with history of any AF than those without, suggesting that patients with AF might derive greater benefits. Further study is warranted to determine the long-term effects of IASD on pulmonary vascular function in HFpEF patients with AF.
Because this study sought to determine pulmonary hemodynamic effects of the IASD, we only included subjects who successfully underwent device implantation and subsequent repeat right heart catheterization, introducing selection bias. Patients with more significant pulmonary vascular disease or RV dysfunction at baseline were excluded from these trials, and these results may not apply to this cohort of patients. Hemodynamics were assessed during supine exercise, and it is unknown whether these results would apply to changes with upright exercise. There was a difference in follow-up right heart catheterization between 2 trials (1 month and 6 months), which might have influenced the results. However, sensitivity analyses showed similar effects of the IASD on pulmonary function in each trial. Changes in pulmonary vascular function over a longer duration of time were not explored and may differ from the effects observed in this study. Because caval blood samples were not obtained during exercise, systemic blood flow was estimated during exercise following IASD using the mixed venous O2 content from the initial exercise study (with septum intact). Although this may have introduced some variability, it seems unlikely that the venous O2 content returning from muscle would have been substantially altered at these workloads. Given the exploratory nature of the analyses, correction for multiple hypothesis testing was not performed.
In addition to LA unloading, creation of a therapeutic left to right shunt is associated with improvements in pulmonary vascular function at rest and during exercise in patients with HF, EF ≥40%, and no significant pulmonary vascular disease or RV dysfunction. Further study is required to identify the mechanisms by which increased pulmonary blood flow improves pulmonary vascular function and to assess the long-term pulmonary vascular effects of this therapy.
COMPETENCY IN MEDICAL KNOWLEDGE: In patients with HFpEF, implantation of a device in the interatrial septum that shunts oxygenated blood from the left atrium to the right (IASD) lowers left atrial pressure, pulmonary vascular resistance and elastance, and increases pulmonary blood flow and pulmonary arterial compliance, without compromising systemic perfusion.
TRANSLATIONAL OUTLOOK: Future studies should clarify the mechanisms by which increased pulmonary blood flow following IASD implantation improves pulmonary vascular function and symptoms in patients with HFpEF and assess the durability of these effects on pulmonary hemodynamics and vascular function.
The Cardiovascular Research Foundation is the recipient of an unrestricted educational grant from Abiomed. Dr. Shah is supported by grants from the National Institutes of Health (R01 HL107577, R01 HL127028, and R01 HL140731) and the American Heart Association (#16SFRN28780016 and #15CVGPSD27260148); has received research grants from Actelion, AstraZeneca, Corvia, and Novartis; and has served as a consultant/Advisory Board/Steering Committee Member for Abbott, Actelion, AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Cardiora, Coridea, CVRx, Eisai, Ionis, Ironwood, Merck, MyoKardia, Novartis, Pfizer, Sanofi, Tenax, and United Therapeutics. Dr. Kaye has served on the Scientific Advisory Board of Corvia. Dr. Gustafsson has served as an unpaid advisor to Corvia; has served as an advisor to Abbott, Pfizer, and Novartis; and has received speaker honoraria from Abbott, Boehringer Ingelheim, Carmat, and Orion. Dr. Komtebedde is an employee of and has equity in Corvia Medical. Dr. Lam has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; and has served on the Advisory Board/Steering Committee/Executive Committee for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research & Development, LLC, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, and Darma. Dr. Burkhoff has served as a consultant to Corvia Medical (Hemodynamic Core Laboratory). Dr. Borlaug is supported by RO1 HL128526 and U10 HL110262. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- heart failure
- heart failure with preserved ejection fraction
- interatrial shunt device
- pulmonary arterial compliance
- pulmonary capillary wedge pressure
- pulmonary vascular resistance
- pulmonary blood flow
- systemic blood flow
- Received June 3, 2019.
- Revision received August 22, 2019.
- Accepted August 26, 2019.
- 2019 American College of Cardiology Foundation
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