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Original Research: Pulmonary Vascular Disease |

Signs of Right Ventricular Deterioration in Clinically Stable Patients With Pulmonary Arterial HypertensionHeart Failure in Pulmonary Arterial Hypertension FREE TO VIEW

Mariëlle C. van de Veerdonk, MD; J. Tim Marcus, PhD; Nico Westerhof, PhD; Frances S. de Man, PhD; Anco Boonstra, MD, PhD; Martijn W. Heymans, PhD; Harm-Jan Bogaard, MD, PhD; Anton Vonk Noordegraaf, MD, PhD
Author and Funding Information

From the Department of Pulmonary Diseases (Drs van de Veerdonk, de Man, Boonstra, Bogaard, and Vonk Noordegraaf), Department of Physics and Medical Technology (Dr Marcus), Department of Physiology (Dr Westerhof), and Department of Biostatistics and Epidemiology (Dr Heymans), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.

CORRESPONDENCE TO: Anton Vonk Noordegraaf, MD, PhD, Department of Pulmonary Diseases, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; e-mail: a.vonk@vumc.nl


FUNDING/SUPPORT: Drs de Man and Vonk Noordegraaf were financially supported by Vidi [91.796.306] and Veni [016.146.099] grants from the Dutch Foundation for Scientific Research (NWO). Drs de Man, Bogaard, and Vonk-Noordegraaf were further supported by CardioVasculair Onderzoek Nederland [CVON 2012-08].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(4):1063-1071. doi:10.1378/chest.14-0701
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BACKGROUND:  Even after years of stable response to therapy, patients with idiopathic pulmonary arterial hypertension (IPAH) may show an unexpected clinical deterioration due to progressive right ventricular (RV) failure. Therefore, the aim of this study was to assess in 5-year clinically stable patients with IPAH whether initial differences or subsequent changes in RV volumes precede late clinical progression.

METHODS:  Included were 22 clinically stable patients with IPAH as reflected by stable or improving New York Heart Association functional class II-III and exercise capacity during 5 years of follow-up. Twelve patients subsequently remained stable during a total follow-up of 10 years, whereas 10 other patients showed late progression leading to death or lung transplantation after a follow-up of 8 years. All patients underwent right-sided heart catheterization and cardiac MRI at baseline and at 1½, 3½, 6½, and, if still alive, 10 years follow-up.

RESULTS:  Baseline hemodynamics were comparable in both groups and remained unchanged during the entire follow-up period. Baseline RV end-systolic volume (RVESV) was higher and RV ejection fraction (RVEF) was lower in late-progressive patients. Late-progressive patients demonstrated a gradually increased RV end-diastolic volume and RVESV and a decline in RVEF, whereas long-term stable patients did not show any RV changes.

CONCLUSIONS:  In patients with stable IPAH for 5 years, subsequent late disease progression is preceded by changes in RV volumes. The results indicate that monitoring RV volumes anticipates clinical worsening, even at a time of apparent clinical stability.

Figures in this Article

In patients with pulmonary arterial hypertension (PAH), increased pulmonary vascular resistance (PVR) and pulmonary artery pressure ultimately result in right ventricular (RV) failure and death.1 Various effective medical therapies have become available allowing prolonged clinical stability and survival. Although a small group of patients may survive longer than 5 years after diagnosis, overall long-term mortality rates are high.2,3 Much is known about the predictors of short-term survival, but predictors of ultimate clinical deterioration in patients with an initially favorable treatment response have not been identified. A clinically stable condition, defined as a stable New York Heart Association (NYHA) functional class II-III and 6-min walk test (6MWT),4 was not associated with better long-term survival,5,6 which might be explained by current medical therapies successfully improving 6MWT and cardiac output (CO) but not necessarily slowing RV failure progression.7,8 If the RV has adverse remodeling during a stable condition, assessment of RV remodeling parameters might predict ultimate disease progression. Therefore, the aim of the present study was to assess whether initial differences or subsequent changes in RV volumes precede clinical deterioration in patients with idiopathic PAH (IPAH) or heritable PAH (HPAH) with a proven 5-year stable clinical condition.

Patients

At the VU University Medical Center, patients received a diagnosis of PAH according to guidelines, including a right-sided heart catheterization (RHC).9 This retrospective analysis of an ongoing prospective study assessed the clinical value of cardiac MRI (CMR) in PAH. During patient selection, we were unaware of RHC and CMR results. Inclusion criteria were (1) diagnosis of IPAH or HPAH; (2) age ≥ 18 years; (3) proven clinically stable condition during the first 5 years of follow-up defined as a stable NYHA functional class II-III and no reduction in the 6MWT ≥ 15%4; (4) CMR, RHC, 6MWT, and NYHA class at baseline and at regular follow-up intervals; and (5) a total follow-up period of 10 years. Therefore, patients with IPAH or HPAH diagnosed between February 1999 and February 2004 were selected and followed until February 2013. The local medical ethics committee approved the study without requirement of a consent statement because the study did not fall within the scope of the Medical Research Involving Human Subjects Act (approval number 2012288).

Application of PAH-targeted medical therapies was performed in-line with guidelines9 and according to availability in The Netherlands. Before 2002, all patients in NYHA functional class III and IV were started on prostacyclins. After 2002, patients in NYHA class II-III were treated with oral medical therapy comprising endothelin receptor antagonists, phosphodiesterase 5 inhibitors, or both either as single-agent therapy or in combination, whereas patients in NYHA class IV received prostacyclins with or without additional oral medical therapies. All patients received anticoagulation and diuretics.

Right-Sided Heart Catheterization

Hemodynamic assessment was performed with a 7F balloon-tipped flow-directed Swan-Ganz catheter (Baxter Healthcare Corp) as described previously.8

Cardiac MRI

CMR was performed on a 1.5-T Sonata or Avanto scanner (Siemens Corporation). CMR data acquisition and postprocessing were performed according to our routine protocol.8 Briefly, during postprocessing using dedicated software, a blinded observer assessed the left ventricular (LV) and RV volumes, mass, and function by manual delineation of the endocardial and epicardial contours on short-axis images. Disc summation was performed according to Simpson’s rule. Stroke volume (SV) was calculated as end-diastolic volume (EDV) − end-systolic volume. Ejection fraction was calculated as (SV/EDV) × 100%. Ventricular relative wall thickness was calculated as ventricular mass divided by EDV.10 Ventricular volumes and masses were indexed to body surface area.

6-Min Walk Test

The 6MWT was performed according to American Thoracic Society guidelines.11

Statistical Analysis

Data are presented as mean ± SD unless stated otherwise. Unpaired Student t tests or Mann-Whitney tests were used to compare continuous variables, and log-linear analysis was performed to compare categorical variables between the two groups at baseline. Linear mixed model analysis was applied to assess the differences between the groups over time. Interaction statistics are presented. Residuals were normally distributed for every tested parameter. Model fit was evaluated, and when necessary, random effects of time variables were corrected for intercepts, slopes, or both. A sensitivity analysis was performed to test whether missing values influenced the results. Data were analyzed using SAS, version 9.2 (SAS Institute Inc) and SPSS, version 20.0 (IBM) software. P < .05 was considered significant.

Patient Selection

Between 1999 and 2004, 48 of 58 patients were selected. Exclusion reasons were no regular CMR due to logistics (n = 4) or claustrophobia (n = 1), follow-up in another hospital (n = 2), development of LV failure (n = 1), and a positive vasodilator challenge (n = 2).9 Twenty-two patients clinically stable for 5 years after diagnosis were enrolled (Fig 1).

Figure Jump LinkFigure 1 –  Study profile. *Excluded due to no regular CMR because of logistical reasons (n = 4) or claustrophobia (n = 1), follow-up in another hospital (n = 2), development of left ventricular failure (n = 1), and a positive vasodilator challenge (n = 2). 6MWT = 6-min walk test; CMR = cardiac MRI; HPAH = heritable pulmonary arterial hypertension; IPAH = idiopathic pulmonary arterial hypertension; NYHA = New York Heart Association; RHC = right-sided heart catheterization.Grahic Jump Location

Twelve of these 22 patients remained clinically stable during the remaining years of follow-up (median, 10 years; interquartile range, 10-11 years) and were labeled as “stable” patients. The other 10 patients showed late clinical disease progression defined as progression to NYHA functional class IV and a reduction in 6MWT > 15%4 after 5 years of initial clinical stability. Patients labeled as “progressive” ultimately either died due to cardiopulmonary causes (n = 6) or underwent lung transplantation (n = 4) by a median of 8 years (interquartile range, 7-10 years) after diagnosis. All patients underwent a complete assessment comprising RHC, CMR, 6MWT, and NYHA class at baseline and after 1.5 ± 0.4, 3.5 ± 0.9, 6.5 ± 1.0, and, if still alive, 10.0 ± 1.2 years of follow-up. Additional 6MWT and NYHA class assessments were performed after 5.0 ± 0.4 years of follow-up.

Demographics

Table 1 shows similar demographics in the stable and progressive patients. Baseline 6MWT was comparable in both groups (P = .321), and most patients were in NYHA functional class III. The 6MWT remained unchanged in both groups during follow-up, and stable NYHA class II-III developed in both groups during the application of medical treatment that persisted during 5 years of follow-up. After 6½ years of follow-up, five progressive patients showed deterioration in NYHA class from II-III to IV (Fig 2).

Table Graphic Jump Location
TABLE 1 ]  Baseline Characteristics

Data are presented as No. or mean ± SD. 6MWT = 6-min walk test; HPAH = heritable pulmonary arterial hypertension; IPAH = idiopathic pulmonary arterial hypertension; NYHA = New York Heart Association.

Figure Jump LinkFigure 2 –  A, The 6MWT was comparable between the stable and progressive patients. B, NYHA functional class improved in both groups after the initiation of medical therapies and persisted during 5 y of follow-up. After 6½ y of follow-up, NYHA class deteriorated in progressive patients. Data are presented as mean ± SEM. *P < .05 between groups. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

During the initial 5 years of clinical stability, no hospitalizations were necessary for RV failure progression, and no IV diuretics were administered. During this time, five stable and three progressive patients received monotherapy, five stable and six progressive patients switched from monotherapy to dual therapy, and one stable patient switched from monotherapy to dual therapy to triple therapy due to lack of clinical improvement. Furthermore, one stable patient received dual therapy, and one progressive patient switched from dual to triple therapy. Overall, treatment regimens were balanced between groups (P = .992).

Baseline Characteristics

Baseline hemodynamics were similar in the two groups (Table 2). RV end-diastolic volume (RVEDV), RV mass, and RV wall thickness were comparable between groups. Progressive patients showed higher RV end-systolic volume (RVESV) and lower RV ejection fraction (RVEF) compared with stable patients (Table 2). No differences in LV parameters were observed between the groups.

Table Graphic Jump Location
TABLE 2 ]  Baseline Hemodynamics and Cardiac Measures

Data are presented as mean ± SD. CMR = cardiac MRI; CO = cardiac output; HR = heart rate; LV = left ventricular; LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; mPAP = mean pulmonary artery pressure; PAWP = pulmonary arterial wedge pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; RHC = right-sided heart catheterization; RV = right ventricular; RVEDV = right ventricular end-diastolic volume; RVEF = right ventricular ejection fraction; RVESV = right ventricular end-systolic volume; SV = stroke volume; Svo2 = mixed venous oxygen saturation.

The 22 patients included in this study showed similar baseline demographics, NYHA functional class, 6MWT results, and hemodynamics compared with the 10 patients who survived 5 years of follow-up but were excluded from study selection (all P > .07) (data not shown).

Changes in Hemodynamics During Follow-up

Mean pulmonary artery pressure remained unchanged in both groups during follow-up (Fig 3). Although absolute values of PVR and CO were different between groups at 1½ years follow-up (both P < .05), the changes in both parameters during 1½ years of follow-up were comparable (PVR P-interaction = .547; CO P-interaction = .821). Furthermore, absolute values of PVR and CO were similar in both groups at 3½ and 6½ years follow-up. Stable patients showed a stronger decrease in right atrial pressure (RAP) than did progressive patients during the first 3½ years of follow-up (P-interaction = .003), but the change in RAP was not different between groups during the overall follow-up period of 6½ years (P-interaction = .274). In both groups, pulmonary arterial wedge pressure, heart rate, and mixed venous oxygen saturation remained, on average, comparable and unchanged during the total follow-up period (data not shown).

Figure Jump LinkFigure 3 –  A, Mean pulmonary artery pressure was comparable between the stable and progressive patients during follow-up. B-D, Pulmonary vascular resistance, cardiac output, and right atrial pressure showed a temporary difference between groups during the first years of follow-up but became equal during the subsequent follow-up intervals. Data are presented as mean ± SEM. *P < .05; **P < .01 between groups.Grahic Jump Location
Changes in Cardiac Wall Thickness, Volumes, and Function During Follow-up

Figure 4 demonstrates that during 6½ years of follow-up, RVEDV and RVESV both continuously increased in the progressive patients (within-group P < .001) but remained unchanged in the stable patients (within-group P > .597) (P-interaction < .006). No differences were observed between groups in the relative RV wall thickness over time. SV remained initially unchanged in both groups but became lower in progressive than in stable patients after 6½ years of follow-up (Fig 5). Progressive patients showed a decline in RVEF during 6½ years of follow-up (P = .008), which was different from the stable patients who showed an initial increase during the first 3½ years of follow-up and a subsequently stable RVEF during 10 years of follow-up (P-interaction = .006).

Figure Jump LinkFigure 4 –  A and B, Right ventricular (RV) end-diastolic volume and RV end-systolic volume increased progressively in the progressive patients but remained unchanged in the stable patients (both P-interaction < .01). C, RV relative wall thickness was comparable in both groups during follow-up. Data are presented as mean ± SEM. *P < .05; **P < .01; ***P < .001 between groups.Grahic Jump Location
Figure Jump LinkFigure 5 –  A, Stroke volume was comparable in the stable and progressive groups during the first 3½ y of follow-up and became lower in the progressive patients after 6½ y of follow-up. B, RV ejection fraction was lower at baseline and showed a gradual decline in the progressive patients during 6½ y of follow-up, whereas it increased in stable patients during the first 3½ y of follow-up that persisted through 10 y of follow-up (P-interaction = .006). Data are presented as mean ± SEM. *P < .05; ***P < .001 between groups. See Figure 4 legend for expansion of abbreviation.Grahic Jump Location

LV end-diastolic volume and the relative LV wall thickness remained comparable in both groups during follow-up (Fig 6). LV end-systolic volume (LVESV) increased in the progressive patients during 6½ years of follow-up (P = .016) and remained unchanged in the stable patients (P = .298). However, the changes in LVESV were not different in both groups during the overall follow-up period (P-interaction = .253). LV ejection fraction (LVEF) remained stable over time in the stable patients and decreased in the progressive patients during 6½ years of follow-up (within-group P = .042). Although the absolute values of LVEF were lower in the progressive patients than in the stable patients at all time points, the changes in LVEF were not significantly different between groups (P-interaction = .196).

Figure Jump LinkFigure 6 –  A, Left ventricular (LV) end-diastolic volume remained low and unchanged in the stable and progressive patients. B, LV end-systolic volume increased in the progressive patients during the last years of follow-up and remained unchanged in the stable patients. C, LV relative wall thickness was similar in the two groups during follow-up. D, LV ejection fraction was higher in the stable patients than in the progressive patients at every follow-up interval. Data are presented as mean ± SEM. *P < .05; **P < .01 between groups.Grahic Jump Location

In a cohort of long-term surviving patients with PAH, we show that RV remodeling can be progressive, even in those who are seemingly clinically stable during 5 to 10 years of follow-up. Moreover, we show that an ultimate disease progression is preceded by changes in RV volumes and RVEF but not by changes in NYHA functional class, exercise capacity, or hemodynamics.

To our knowledge, this study provides the first phenotypic descriptions of patients with PAH who show an initially favorable treatment response and survive for at least 5 years after diagnosis. Corresponding to previous results, we show that improvements in CO and RAP during the first years of follow-up are associated with survival.12 However, in-line with former studies, the present results demonstrate that patients with an initially favorable treatment response show no further hemodynamic changes during long-term follow-up, regardless of the final outcome.13,14 These findings suggest that long-term treatment with PAH-specific vasodilator therapies might halt some of the progressive pulmonary vascular remodeling and may account for the improved outcomes in the current treatment era.14

The most important finding of the present study was that increasing RV volumes during a clinically stable period preceded ultimate clinical deterioration. The absolute differences in RV volumes between stable and progressive patients with PAH gradually increased over time, which implies that the changes in RV volumes could be sensitive parameters to monitor patients during follow-up. The importance of progressive cardiac remodeling during clinical stable disease is in line with previous findings. In studies focusing on LV failure, increased LV volumes in asymptomatic patients were independent predictors of symptomatic heart failure and mortality.1517 Other LV studies found that LV remodeling could progress despite the application of medical therapies aiming to preserve CO and clinical stability.18 Similarly, it has been demonstrated that current PAH vasodilator medical therapies significantly improve CO but may have limited effects on RV adaptation and remodeling.19

We observed a lower baseline RVEF and a decline in RVEF in the progressive patients during follow-up but not in the stable patients. These findings correspond with previous studies showing that a low and decreasing RVEF is a strong prognostic predictor.8,20

Assessment of RV remodeling is not only of prognostic importance8,20 but also of physiologic interest. The progressive patients showed a larger RVEDV and RVESV and lower RVEF than the stable patients. In the absence of differences in RV load, it is likely that this adverse RV remodeling pattern was the consequence of a poor ability of the right ventricle to adapt to the increased afterload. In the context of an increased RV load and insufficient improvement of RV systolic elastance (right ventricle-arterial uncoupling), RVESV is expected to increase, and this will be followed by a reduction in RVEF.2124 In addition, although an increase in EDV may help to normalize SV in the setting of contractile dysfunction through the Frank-Starling mechanism,24 the law of Laplace predicts that this will be accompanied by an increase in RV wall stress with harmful effects on the right ventricle in the long run. RV wall thickness remained unchanged during follow-up in the present study and was probably insufficient to lower the wall stress.25 In addition, other factors could play a role in a distinct RV adaptation response, such as metabolism, neurohormones, inflammation, ischemia, and genetics.26,27

Compared with LV reference values28 and in line with previous studies in PAH,20,2931 LV filling dimensions in the present two PAH patient groups were low. Impaired LV filling could be explained by direct ventricular interaction due to interventricular dyssynchrony and leftward septum bowing31,32 or by a low RV output resulting in LV underfilling. Strikingly, at every measured time point, LV systolic function was lower in the progressive patients than in the stable patients. This may be a result of reduced LV preload, but previous studies have also demonstrated by LV strain imaging that LV contractility and LV torsion are impaired in patients with PAH.29,31 Furthermore, according to the LV pressure-volume relationship, an increased LVESV is associated with impaired LV contractility.

Clinical Implications

We show that in long-term PAH survivors, a clinically stable profile and preserved CO may mask RV failure progression and that changes in RV volumes may be sensitive parameters to predict an ultimate deterioration, even at a time of clinical stability. The results indicate that evaluation of RV volumes and RVEF is important to detect early development of heart failure and to permit timely intervention. The results also raise the question of whether prognosis can be improved by a goal-oriented strategy using RV rather than clinical parameters as the treatment goal. The findings of an ultimate similarity in PVR in stable and progressive patients also begs the question of whether late disease progression could have been prevented by more-aggressive vasodilator treatment or, rather, by a treatment specifically directed at improving RV adaptation. In contrast with patients who died soon after diagnosis, the progressive patients did not show a severely disturbed hemodynamic profile, not even in the last measurement before death. Because hemodynamic progression can be very rapid in end-stage disease, it is likely that had RHC been performed in the days to weeks prior to death, results would have been much worse. In contrast, the considerable RV dilatation observed in the late-progressive patients is infrequently encountered in patients with shorter survival periods,8,20 suggesting that extensive RV remodeling takes years to develop. Importantly, these observations imply that the long-term follow-up results of the present study cannot be extrapolated to patients with a more severe hemodynamic profile shortly after diagnosis.

Limitations

Although we included a small patient population, clear differences between study groups were found with high levels of statistical significance. Previously, Addetia et al33 demonstrated that to detect specific changes in RV volumes and function by CMR in patients with PAH, a small sample size is sufficient to achieve adequate statistical power. Death and lung transplantation together were used as a composite end point to define late progression. When only nonsurvivors were included in the analysis, we found similar results, with more pronounced absolute differences between the stable and progressive groups (data not shown).

Because we used long-term survival as an inclusion criterion, patients who died during the first years of follow-up were not included, leading to immortal time bias.34 In addition, although the prescribed therapies in this study are still considered effective therapies and recommended by the current guidelines,9 at present, these therapies are more frequently applied in combination treatment schedules. Instead, single-agent therapy was more common during the inclusion of the present study patients.

During the first years of follow-up, measurements of N-terminal pro-brain natriuretic peptide (NT-proBNP) were unavailable in The Netherlands and, therefore, not included. Former studies have shown that although NT-proBNP level contains prognostic information, a sufficient increase is required to be of clinical relevance.6,35 Further studies are required to test the sensitivity of early changes in NT-proBNP levels to detect ultimate disease progression.

RV volumes and RVEF can deteriorate in apparently stable patients with IPAH or HPAH, and changes in these parameters precede ultimate disease progression and mortality. The results imply that monitoring of RV remodeling is essential to detecting early development of heart failure and to permitting timely intervention, even at a time of clinical stability.

Author contributions: M. C. v. d. V. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. M. C. v. d. V., H.-J. B., and A. V. N. contributed to the study concept and design; J. T. M., N. W., F. S. d. M., A. B., and M. W. H. contributed to the data acquisition and data analysis and interpretation; and M. C. v. d. V., J. T. M., N. W., F. S. d. M., A. B., M. W. H., H.-J. B., and A. V. N. contributed to drafting the manuscript or revising it critically for important intellectual content.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Marcus has a consultancy agreement with Actelion Pharmaceuticals Ltd. Dr Boonstra has or had financial relationships with companies including, but not limited to, Actelion Pharmaceuticals Ltd; Pfizer, Inc; Teva Pharmaceutical Industries Ltd; Sun Pharmaceuticals Industries Ltd; Bayer HealthCare AG; United Therapeutics Corporation; THERABEL Group; Ferrer Internacional; Boehringer Ingelheim GmbH; GlaxoSmithKline plc; mondoBIOTECH Holding AG; and Chiesi Pharmaceuticals BV. In addition to being an investigator in trials involving these companies, relationships include financial reimbursement for consultancy service, membership on scientific advisory boards, and speaker fees. All payments from 2012 larger than €500 can be found on www.transparantieregister.nl under number 59020144101. Dr Bogaard has received research support from Boehringer Ingelheim GmbH; speaker fees from Bayer HealthCare AG and Pfizer, Inc; and consulting fees from Bayer HealthCare AG, United Therapeutics Corporation, and Actelion Pharmaceuticals Ltd. Dr Vonk Noordegraaf has received lecture fees from Actelion Pharmaceuticals Ltd; Bayer HealthCare AG; GlaxoSmithKline plc; Eli Lilly and Company; and Pfizer, Inc, and served on industry advisory boards for Actelion Pharmaceuticals Ltd and Bayer HealthCare AG and on steering committees for Actelion Pharmaceuticals Ltd; Bayer HealthCare AG; and Pfizer, Inc. Drs van de Veerdonk, Westerhof, de Man, and Heymans have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

6MWT

6-min walk test

CMR

cardiac MRI

CO

cardiac output

EDV

end-diastolic volume

HPAH

heritable pulmonary arterial hypertension

IPAH

idiopathic pulmonary arterial hypertension

LV

left ventricular

LVEF

left ventricular ejection fraction

LVESV

left ventricular end-systolic volume

NT-proBNP

N-terminal pro-brain natriuretic peptide

NYHA

New York Heart Association

PAH

pulmonary arterial hypertension

PVR

pulmonary vascular resistance

RAP

right atrial pressure

RHC

right-sided heart catheterization

RV

right ventricular

RVEDV

right ventricular end-diastolic volume

RVEF

right ventricular ejection fraction

RVESV

right ventricular end-systolic volume

SV

stroke volume

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van Wolferen SA, Marcus JT, Boonstra A, et al. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J. 2007;28(10):1250-1257. [CrossRef] [PubMed]
 
Vonk-Noordegraaf A, Westerhof N. Describing right ventricular function. Eur Respir J. 2013;41(6):1419-1423. [CrossRef] [PubMed]
 
Tedford RJ, Mudd JO, Girgis RE, et al. Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension. Circulation Heart Fail. 2013;6(5):953-963. [CrossRef]
 
Kuehne T, Yilmaz S, Steendijk P, et al. Magnetic resonance imaging analysis of right ventricular pressure-volume loops: in vivo validation and clinical application in patients with pulmonary hypertension. Circulation. 2004;110(14):2010-2016. [CrossRef] [PubMed]
 
Sagawa K, Maughan L, Suga H, Sunagawa K. Cardiac Contraction and the Pressure-Volume Relationship. New York, NY: Oxford University Press; 1988.
 
Simon MA, Deible C, Mathier MA, et al. Phenotyping the right ventricle in patients with pulmonary hypertension. Clin Transl Sci. 2009;2(4):294-299. [CrossRef] [PubMed]
 
Rain S, Handoko ML, Trip P, et al. Right ventricular diastolic impairment in patients with pulmonary arterial hypertension. Circulation. 2013;128(18):2016-2025. [CrossRef] [PubMed]
 
Voelkel NF, Gomez-Arroyo J, Abbate A, Bogaard HJ. Mechanisms of right heart failure-a work in progress and a plea for failure prevention. Pulm Circ. 2013;3(1):137-143. [CrossRef] [PubMed]
 
Natori S, Lai S, Finn JP, et al. Cardiovascular function in multi-ethnic study of atherosclerosis: normal values by age, sex, and ethnicity. AJR Am J Roentgenol. 2006;186(6_suppl_2):S357-S365. [CrossRef] [PubMed]
 
Hardegree EL, Sachdev A, Fenstad ER, et al. Impaired left ventricular mechanics in pulmonary arterial hypertension: identification of a cohort at high risk. Circ Heart Fail. 2013;6(4):748-755. [CrossRef] [PubMed]
 
Tonelli AR, Plana JC, Heresi GA, Dweik RA. Prevalence and prognostic value of left ventricular diastolic dysfunction in idiopathic and heritable pulmonary arterial hypertension. Chest. 2012;141(6):1457-1465. [CrossRef] [PubMed]
 
Puwanant S, Park M, Popović ZB, et al. Ventricular geometry, strain, and rotational mechanics in pulmonary hypertension. Circulation. 2010;121(2):259-266. [CrossRef] [PubMed]
 
Marcus JT, Gan CT, Zwanenburg JJ, et al. Interventricular mechanical asynchrony in pulmonary arterial hypertension: left-to-right delay in peak shortening is related to right ventricular overload and left ventricular underfilling. J Am Coll Cardiol. 2008;51(7):750-757. [CrossRef] [PubMed]
 
Addetia K, Bhave NM, Tabit CE, et al. Sample size and cost analysis for pulmonary arterial hypertension drug trials using various imaging modalities to assess right ventricular size and function end points. Circ Cardiovasc Imaging. 2014;7(1):115-124. [CrossRef] [PubMed]
 
Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol. 2008;167(4):492-499. [CrossRef] [PubMed]
 
Mauritz GJ, Rizopoulos D, Groepenhoff H, et al. Usefulness of serial N-terminal pro-B-type natriuretic peptide measurements for determining prognosis in patients with pulmonary arterial hypertension. Am J Cardiol. 2011;108(11):1645-1650. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Study profile. *Excluded due to no regular CMR because of logistical reasons (n = 4) or claustrophobia (n = 1), follow-up in another hospital (n = 2), development of left ventricular failure (n = 1), and a positive vasodilator challenge (n = 2). 6MWT = 6-min walk test; CMR = cardiac MRI; HPAH = heritable pulmonary arterial hypertension; IPAH = idiopathic pulmonary arterial hypertension; NYHA = New York Heart Association; RHC = right-sided heart catheterization.Grahic Jump Location
Figure Jump LinkFigure 2 –  A, The 6MWT was comparable between the stable and progressive patients. B, NYHA functional class improved in both groups after the initiation of medical therapies and persisted during 5 y of follow-up. After 6½ y of follow-up, NYHA class deteriorated in progressive patients. Data are presented as mean ± SEM. *P < .05 between groups. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3 –  A, Mean pulmonary artery pressure was comparable between the stable and progressive patients during follow-up. B-D, Pulmonary vascular resistance, cardiac output, and right atrial pressure showed a temporary difference between groups during the first years of follow-up but became equal during the subsequent follow-up intervals. Data are presented as mean ± SEM. *P < .05; **P < .01 between groups.Grahic Jump Location
Figure Jump LinkFigure 4 –  A and B, Right ventricular (RV) end-diastolic volume and RV end-systolic volume increased progressively in the progressive patients but remained unchanged in the stable patients (both P-interaction < .01). C, RV relative wall thickness was comparable in both groups during follow-up. Data are presented as mean ± SEM. *P < .05; **P < .01; ***P < .001 between groups.Grahic Jump Location
Figure Jump LinkFigure 5 –  A, Stroke volume was comparable in the stable and progressive groups during the first 3½ y of follow-up and became lower in the progressive patients after 6½ y of follow-up. B, RV ejection fraction was lower at baseline and showed a gradual decline in the progressive patients during 6½ y of follow-up, whereas it increased in stable patients during the first 3½ y of follow-up that persisted through 10 y of follow-up (P-interaction = .006). Data are presented as mean ± SEM. *P < .05; ***P < .001 between groups. See Figure 4 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 6 –  A, Left ventricular (LV) end-diastolic volume remained low and unchanged in the stable and progressive patients. B, LV end-systolic volume increased in the progressive patients during the last years of follow-up and remained unchanged in the stable patients. C, LV relative wall thickness was similar in the two groups during follow-up. D, LV ejection fraction was higher in the stable patients than in the progressive patients at every follow-up interval. Data are presented as mean ± SEM. *P < .05; **P < .01 between groups.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Baseline Characteristics

Data are presented as No. or mean ± SD. 6MWT = 6-min walk test; HPAH = heritable pulmonary arterial hypertension; IPAH = idiopathic pulmonary arterial hypertension; NYHA = New York Heart Association.

Table Graphic Jump Location
TABLE 2 ]  Baseline Hemodynamics and Cardiac Measures

Data are presented as mean ± SD. CMR = cardiac MRI; CO = cardiac output; HR = heart rate; LV = left ventricular; LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; mPAP = mean pulmonary artery pressure; PAWP = pulmonary arterial wedge pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; RHC = right-sided heart catheterization; RV = right ventricular; RVEDV = right ventricular end-diastolic volume; RVEF = right ventricular ejection fraction; RVESV = right ventricular end-systolic volume; SV = stroke volume; Svo2 = mixed venous oxygen saturation.

References

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Handoko ML, de Man FS, Allaart CP, Paulus WJ, Westerhof N, Vonk-Noordegraaf A. Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart. Eur Respir Rev. 2010;19(115):72-82. [CrossRef] [PubMed]
 
van Wolferen SA, Marcus JT, Boonstra A, et al. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J. 2007;28(10):1250-1257. [CrossRef] [PubMed]
 
Vonk-Noordegraaf A, Westerhof N. Describing right ventricular function. Eur Respir J. 2013;41(6):1419-1423. [CrossRef] [PubMed]
 
Tedford RJ, Mudd JO, Girgis RE, et al. Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension. Circulation Heart Fail. 2013;6(5):953-963. [CrossRef]
 
Kuehne T, Yilmaz S, Steendijk P, et al. Magnetic resonance imaging analysis of right ventricular pressure-volume loops: in vivo validation and clinical application in patients with pulmonary hypertension. Circulation. 2004;110(14):2010-2016. [CrossRef] [PubMed]
 
Sagawa K, Maughan L, Suga H, Sunagawa K. Cardiac Contraction and the Pressure-Volume Relationship. New York, NY: Oxford University Press; 1988.
 
Simon MA, Deible C, Mathier MA, et al. Phenotyping the right ventricle in patients with pulmonary hypertension. Clin Transl Sci. 2009;2(4):294-299. [CrossRef] [PubMed]
 
Rain S, Handoko ML, Trip P, et al. Right ventricular diastolic impairment in patients with pulmonary arterial hypertension. Circulation. 2013;128(18):2016-2025. [CrossRef] [PubMed]
 
Voelkel NF, Gomez-Arroyo J, Abbate A, Bogaard HJ. Mechanisms of right heart failure-a work in progress and a plea for failure prevention. Pulm Circ. 2013;3(1):137-143. [CrossRef] [PubMed]
 
Natori S, Lai S, Finn JP, et al. Cardiovascular function in multi-ethnic study of atherosclerosis: normal values by age, sex, and ethnicity. AJR Am J Roentgenol. 2006;186(6_suppl_2):S357-S365. [CrossRef] [PubMed]
 
Hardegree EL, Sachdev A, Fenstad ER, et al. Impaired left ventricular mechanics in pulmonary arterial hypertension: identification of a cohort at high risk. Circ Heart Fail. 2013;6(4):748-755. [CrossRef] [PubMed]
 
Tonelli AR, Plana JC, Heresi GA, Dweik RA. Prevalence and prognostic value of left ventricular diastolic dysfunction in idiopathic and heritable pulmonary arterial hypertension. Chest. 2012;141(6):1457-1465. [CrossRef] [PubMed]
 
Puwanant S, Park M, Popović ZB, et al. Ventricular geometry, strain, and rotational mechanics in pulmonary hypertension. Circulation. 2010;121(2):259-266. [CrossRef] [PubMed]
 
Marcus JT, Gan CT, Zwanenburg JJ, et al. Interventricular mechanical asynchrony in pulmonary arterial hypertension: left-to-right delay in peak shortening is related to right ventricular overload and left ventricular underfilling. J Am Coll Cardiol. 2008;51(7):750-757. [CrossRef] [PubMed]
 
Addetia K, Bhave NM, Tabit CE, et al. Sample size and cost analysis for pulmonary arterial hypertension drug trials using various imaging modalities to assess right ventricular size and function end points. Circ Cardiovasc Imaging. 2014;7(1):115-124. [CrossRef] [PubMed]
 
Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol. 2008;167(4):492-499. [CrossRef] [PubMed]
 
Mauritz GJ, Rizopoulos D, Groepenhoff H, et al. Usefulness of serial N-terminal pro-B-type natriuretic peptide measurements for determining prognosis in patients with pulmonary arterial hypertension. Am J Cardiol. 2011;108(11):1645-1650. [CrossRef] [PubMed]
 
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