Author + information
- Received May 15, 2014
- Revision received July 8, 2014
- Accepted July 28, 2014
- Published online January 1, 2015.
- Emmanouil Tampakakis, MD∗,
- Peter J. Leary, MD, MS†,
- Van N. Selby, MD‡,
- Teresa De Marco, MD‡,
- Thomas P. Cappola, MD, ScM§,
- G. Michael Felker, MD, MHS‖,
- Stuart D. Russell, MD∗,
- Edward K. Kasper, MD∗ and
- Ryan J. Tedford, MD∗∗ ()
- ∗Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland
- †Division of Pulmonary and Critical Care, University of Washington, Seattle, Washington
- ‡Division of Cardiology, University of California-San Francisco, San Francisco, California
- §Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
- ‖Division of Cardiology, Duke University Medical Center, Durham, North Carolina
- ↵∗Reprint requests and correspondence:
Dr. Ryan J. Tedford, Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, 568 Carnegie, 600 North Wolfe Street, Baltimore, Maryland 21287.
Objectives This study sought to evaluate if diastolic pulmonary gradient (DPG) can predict survival in patients with pulmonary hypertension due to left heart disease (PH-LHD).
Background Patients with combined post- and pre-capillary PH-LHD have worse prognosis than those with passive pulmonary hypertension. The transpulmonary gradient (TPG) and pulmonary vascular resistance (PVR) have commonly been used to identify high-risk patients. However, these parameters have significant shortcomings and do not always correlate with pulmonary vasculature remodeling. Recently, it has been suggested that DPG may be better a marker, yet its prognostic ability in patients with cardiomyopathy has not been fully assessed.
Methods A retrospective cohort of 1,236 patients evaluated for unexplained cardiomyopathy at Johns Hopkins Hospital was studied. All patients underwent right heart catheterization and were followed until death, cardiac transplantation, or the end of the study period (mean time 4.4 years). The relationships between DPG, TPG, or PVR and survival in subjects with PH-LHD (n = 469) were evaluated with Cox proportional hazards regression and Kaplan-Meier analyses.
Results DPG was not significantly associated with mortality (hazard ratio [HR]: 1.02, p = 0.10) in PH-LHD whereas elevated TPG and PVR predicted death (HR: 1.02, p = 0.046; and HR: 1.11, p = 0.002, respectively). Similarly, DPG did not differentiate survivors from non-survivors at any selected cut points including a DPG of 7 mm Hg.
Conclusions In this retrospective study of patients with cardiomyopathy and PH-LHD, an elevated DPG was not associated with worse survival.
Patients with pulmonary hypertension (PH) due to left heart disease (PH-LHD), defined as pulmonary capillary wedge pressure (PCWP) >15 mm Hg and mean pulmonary artery pressure (mPAP) ≥25 mm Hg, have worse prognosis compared to those without PH (1). Among those patients with PH, 2 phenotypes have been described: 1) a group of isolated post-capillary or “passive” PH in which elevated pulmonary pressures are reversible and in proportion to increases in left atrial pressure; and 2) a group with “pre-capillary” component (combined post-capillary and pre-capillary pulmonary hypertension [CpcPH]) whose pulmonary hypertension is worse than can be fully explained by passive elevation secondary to elevated left atrial pressure. This latter group may have comorbid pulmonary vascular remodeling and therefore may demonstrate persistent PH after interventions to lower left-sided filling pressures. The ability to accurately define and separate a high-risk subgroup has major implications in the management and outcomes of heart failure patients as those with CpcPH due to left heart disease have worse prognosis (1,2) and may not be suitable for cardiac transplantation (2).
In an effort to better characterize the 2 populations, several hemodynamic parameters have been used. A transpulmonary gradient (TPG), mPAP-PCWP, >12 to 15 mm Hg and a pulmonary vascular resistance (PVR), TPG/cardiac output, >2.5 to 3 Wood units have been used to describe patients with “out of proportion”: or those with a pre-capillary component to PH (1). TPG however, is flow dependent (3) and influenced by elevation in left atrial pressure (4), making it an unreliable marker of the pulmonary vascular contribution to PH-LHD. Although not without limitations, most favor PVR to identify high-risk patients. Our group and others have shown that elevated PVR predicts outcomes in patients with PH-LHD better than TPG (5–7).
More recently diastolic pulmonary gradient (DPG), diastolic pulmonary artery pressure (dPAP) minus PCWP has been proposed to distinguish CpcPH from isolated post-capillary PH (3,8). Elevated DPG (≥7 mm Hg) may be associated with pulmonary vascular remodeling and predict worse survival in individuals with elevated TPG and PH-LHD (9). We have previously shown, however, that DPG is not associated with death after heart transplant, which may call into question the assertion that DPG is a strong marker of intrinsic pulmonary vascular disease in PH-LHD (10). In this study, we sought to determine whether an elevated DPG predicted survival using a cohort of 1,236 patients previously evaluated for unexplained cardiomyopathy (5).
Study subjects included inpatients and outpatients referred to the Johns Hopkins Hospital Cardiomyopathy Service for further evaluation of heart failure due to undiagnosed cardiomyopathy. All patients received treatment of their heart failure prior to undergoing right heart catheterization and biopsy. A total of 1,236 patients were evaluated between December 1982 and December 1997 as previously described (11). All patients underwent extensive work up, which included endomyocardial biopsy with right heart catheterization by a heart failure cardiologist and coronary angiography when indicated. After the evaluation, all patients were assigned a cause of cardiomyopathy. Age, gender, race, height, and weight were recorded at the time of their initial evaluation. The patients were followed until death, cardiac transplantation, or the end of the study period (January 1, 1998). Vital status was obtained from medical records and through a search of the Nation Death Index (12). The study was approved by the Joint Committee on Clinical Investigation at Johns Hopkins Hospital. All patients provided informed consent to use their data in the study.
Right heart catheterization
Patients underwent right heart catheterization by heart failure specialists at the Johns Hopkins catheterization laboratory with a balloon-tipped, flow-directed catheter placed into the right internal jugular vein. Hemodynamics were measured at the time of presentation before optimizing medical therapy. Cardiac output was determined as the mean of 3 to 5 separate measurements with the thermodilution method. Systemic arterial pressure was measured noninvasively. Mean right atrial pressure, systolic pulmonary artery pressure, dPAP, mPAP, and PCWP were recorded at end expiration. PVR was calculated in Wood units as the difference between mPAP and PCWP divided by cardiac output. TPG was calculated as the difference between mPAP and PCWP. DPG was calculated as the difference between the dPAP and PCWP.
Comparison of groups was performed with a Mann-Whitney rank sum test or, for multiple groups, by 1-way analysis of variance. Categorical variables were compared with chi-square test. Hazard ratios (HRs) of death for DPG, TPG, and PVR were estimated with Cox proportional hazards regression analysis in all patients with PH-LHD (PCWP >15 mm Hg and mPAP ≥25 mm Hg). The primary endpoint was death from all causes. Participants who underwent transplantation (n = 36 of 469) were censored at the time of transplantation. Unadjusted and adjusted models for age, gender, race and body mass index were considered. For our sample size (n = 469) and mortality rate (43%), we had adequate power (80%) to detect a 10% or smaller difference in the hazard of death for all of the evaluated hemodynamic parameters. While we might have been underpowered to detect smaller differences in the hazard of death, such small difference in mortality would argue against the use of these parameters to discriminate survivors. Survival was also estimated with the nonparametric methods of Kaplan and Meier and compared using the log-rank test. A p value (2-tailed) of <0.05 was considered significant. Medians are presented with interquartile range. Statistical analyses were performed using STATA version 12 (Stata Corp., College Station, Texas) and SigmaPlot version 11.0 (Systat Software Inc., San Jose, California).
Among 1,236 patients who were evaluated with a right heart catheterization for a new diagnosis of heart failure, 1,174 had a complete set of hemodynamics. Most patients had diagnosis of a dilated cardiomyopathy. Of the 1,174 patients, 558 had an elevated PCWP >15 mm Hg. Of those, 469 had mPAP ≥25 mm Hg consistent with PH-LHD. Also, 650 patients did not have PH (mPAP <25 mm Hg). Of the 1,174 patients, 124 (10.6 %) had a DPG ≥7 mm Hg, and, of those, 92 (74.2%) also had PH and 62 (50.0%) had PH-LHD. Therefore, 32 patients without PH (mPAP <25 mm Hg) had a DPG ≥7 mm Hg. In addition, 355 (30.2%) of all patients evaluated and 169 (36.0%) of the subjects with PH-LHD had a negative DPG value. The clinical characteristics and hemodynamics of those patients with a negative DPG are found in Online Table 1. On average, the negative DPG group had worse hemodynamics, as evidenced by lower right and left ventricular stroke work index and higher PCWP.
Association between DPG, TPG, or PVR and death in PH-LHD
DPG was not significantly associated with mortality in unadjusted (HR: 1.02, p = 0.08) analysis or after adjusting for age, gender, race, and body mass index (HR: 1.02, p = 0.10) (Table 1). TPG was associated with mortality (unadjusted HR: 1.02, p = 0.03) and was borderline significant after adjustment (HR: 1.02, p = 0.046). PVR predicted mortality in our cohort (unadjusted HR: 1.13, p = 0.002; adjusted HR: 1.11, p = 0.002) (Table 1). Because DPG, TPG, and PVR have different units, qualitative comparison of HRs per unit change is difficult. Reparameterization of markers by interquartile range allowed comparison between markers. The hazard of mortality appeared more similar in this context; however, the strength of association with reparameterization is not changed and the association with mortality remained strongly significant for PVR, of borderline significance for TPG, and not significant for DPG.
Survival in patients with PH-LHD and elevated DPG
In keeping with the results of the Cox analysis, there was no statistical difference in mortality between high (defined as ≥1, ≥3, ≥5, ≥7, or ≥9 mm Hg) and low DPG groups (<1, <3, <5, <7, or <9 mm Hg) (Table 2). We further examined the cutoff of 7 mm Hg, which has previously been shown to be a surrogate marker for CpcPH (9) and has been proposed for clinical use (8). Demographic, diagnostic and hemodynamic data for those subjects (DPG <7 and DPG ≥7 mm Hg) as well as the 650 patients without PH are presented in Table 3. Demographic and heart failure diagnosis were similar between the high and low DPG groups. Compared with the lower DPG group (<7 mm Hg), patients with DPG ≥7 mm Hg had higher systemic and pulmonary artery pressures, higher right and left ventricular stroke work index, and higher PVR. Patients with a lower DPG had a higher PCWP (26 vs. 22 mm Hg; p < 0.001). No difference in survival between the 2 groups at a mean follow-up time of 4.4 years was observed (Figure 1A).
Survival in patients with PH-LHD and elevated TPG or PVR
After exploring various TPG cutoff points (high defined as >6, >9, >12, or 15 mm Hg and low defined as ≤6, ≤9, ≤12, or ≤15 mm Hg), a TPG >9 mm Hg significantly differentiated survivors from nonsurvivors (Table 4). In a subcohort of patients with TPG >12 mm Hg (n = 151), higher DPG (≥7 mm Hg) was not associated with increased mortality (Figure 1B).
All PVR cutpoints explored (low defined as <2, <2.5, <3, or <3.5 and high defined as ≥2, ≥2.5, ≥3, or ≥3.5 Wood units) predicted worse survival in the original cohort (Table 4). In exploratory models, PVR was considered as an effect modifier of the relationship between DPG or TPG and death. PVR did not significantly modify the association between TPG and death (p for interaction = 0.13). PVR did modify the association between DPG and death such that increasing DPG decreased the hazard of death at high levels of PVR (p for interaction = 0.02; interaction term HR: 0.98). Similarly, Figure 1C suggests that in subjects with PVR ≥3 mm Hg (n = 179), those subjects with a low DPG (<7 mm Hg) trended toward worse survival compared with high DPG (≥7 mm Hg; p = 0.051). The number of participants at risk in these exploratory subgroup analyses was relatively small and estimates of association may be unstable.
Removing patients with HIV diagnosis (who had an overall worse prognosis during this study period), those with an infiltrative disease (amyloid/sarcoid), and those with a diagnosis of restrictive cardiomyopathy left a cohort of 419 PH-LHD patients. DPG also did not predict survival in this cohort (Online Table 2).
In the present study, we used a well-characterized, large cohort of patients previously evaluated by the cardiomyopathy service at Johns Hopkins Hospital with right heart catheterization and cardiac biopsy (5), to assess the ability of DPG to predict mortality. DPG used independently or in combination with elevated TPG or PVR and in either unadjusted or adjusted analyses, failed to predict mortality in patients with PH-LHD. Conversely, PVR was associated with decreased survival in all analyses in subjects with PH-LHD, similar to prior analyses (6,7,13).
In PH-LHD, elevated left heart filling pressures are transmitted to the pulmonary veins and lead to increased dPAP. Persistent pulmonary venous congestion results in endothelial dysfunction with decreased nitric oxide production and increased production of vasoactive factors (e.g., endothelin-1, angiotensin II) favoring vasoconstriction, and may ultimately lead to irreversible remodeling of the pulmonary vasculature (8,14). Elevation in left atrial pressure also leads to increased vascular stiffness (decreased compliance). This results in an increased systolic pulmonary artery pressure, and therefore mPAP, leading to elevation of TPG as well as PVR (4,14). Both of these factors depend on the flow (cardiac output) (3). The dPAP, however, is less sensitive to these effects, and therefore DPG (dPAP minus PCWP) has been recommended as an alternative and more reliable marker of PH-LHD with a pre-capillary component (8).
The prognostic capability of DPG in patients with CpcPH was recently evaluated in a cohort of 1,094 patients with PH-LHD. In this study by Gerges et al. (9), participants with a TPG >12 mm Hg and a DPG ≥7 mm Hg had worse survival compared to those with a TPG ≤12 mm Hg and a DPG <7 mm Hg. In 18 of these participants, lung tissue was evaluated and participants with elevated DPG had advanced remodeling of the pulmonary vasculature (9). This study coupled with sound physiologic reasoning has led to the recent recommendations from the Fifth World Symposium on Pulmonary Hypertension that DPG be the sole discriminator of pre- and post-capillary PH in those with left heart disease (8). Our heart failure cohort was significantly different from the study population of Gerges et al. (9) as it had relatively lower incidence of PH (44% vs. 91%) Our patients were also younger and were less likely to have an ischemic cardiomyopathy. When considering only the PH-LHD patients, the distribution of CpcPH (TPG >12 mm Hg) was relatively similar (32% vs. 45%).
Using the United Network of Organ Sharing database, we recently demonstrated that elevated pre-transplant DPG had no association with post-transplant survival (10). These findings argued against DPG as a marker of clinically significant irreversible pulmonary vascular remodeling, although they did not necessarily exclude the possibility that DPG could predict outcomes in a heart failure population that did not undergo transplant. Unfortunately, the findings of the current study do not support the use of DPG in this regard. DPG was not associated with survival in any analysis and high DPG may have even been a marker of better prognosis in an exploratory subgroup of CpcPH with high PVR. The lack of association or even inverse association with mortality may be related to the important observation in our cohort that low DPG may have identified a sicker group of patients with a higher PCWP and lower systemic blood pressure. This was true in both the entire cohort of 1,174 patients as well as those only with PH-LHD.
Despite its promise, the use of DPG has significant shortcomings and limitations. The DPG may be particularly susceptible to technical errors. Measurement of dPAP, particularly when using fluid filled catheters, is subject to error from catheter motion artifacts. This likely accounts for the negative DPG values observed in our study as well as others. In a study of critically ill patients by Wilson et al. (15), the DPG was negative in 18.5% of the readings. Similar results have been reported after coronary artery bypass surgery (16). Moreover, in a classic investigation by Harvey et al. (17), patients with left heart disease had a mean DPG of –2 mm Hg. Even small errors in the measurement of dPAP or PCWP will have a major impact on the DPG given its relatively low absolute value. As previously highlighted by Ryan et al. (18), the use of computerized mean PCWP pressures averaged throughout the respiratory cycle rather than end-expiratory measurements leads to an underestimation of the true PCWP, particularly in patients with higher intrathoracic pressures. In addition, inaccurate wedging of the pulmonary artery catheter can overestimate PCWP leading to falsely low DPG. Finally, DPG itself accounts for only a small proportion of total right ventricular load in patients with PH-LHD and therefore may not be necessarily associated with significant right ventricular dysfunction. Right ventricular function is a well-known prognosticator of outcomes in heart failure, and therefore, PVR may be a superior prognosticator because it includes flow assessment (19). However, even in patients with an elevated PVR, an elevated DPG was not associated with worse prognosis.
The use of DPG in PH is not new and it was extensively studied in previous decades (15,17,20). Many factors other than pulmonary vascular remodeling also affect the DPG. DPG is acutely elevated in several different clinical scenarios including hypoxemia in patients with acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD) (17,21,22), after coronary artery bypass surgery (15), and in sepsis due to acidosis, release of endotoxins, or microthrombi (17,23). Tachycardia, which is commonly encountered in individuals with LHD due to decreased cardiac output, tachyarrhythmias, or inotropic support, also increases the DPG (24).
We acknowledge that our retrospective study has several limitations. First, our cohort included patients evaluated for unexplained cardiomyopathy with a broad representation of different heart failure pathologies, which may not necessarily represent the general heart failure population. Although this cohort consisted of patients with both preserved and reduced function, most patients had a diagnosis of a dilated cardiomyopathy, leaving open the possibility that DPG may have a prognostic ability in heart failure with preserved ejection fraction, or in a more select group of heart failure patients. Because the incidence of PH-LHD was relatively low in our population (44%), this could limit our power to detect a difference in survival between the low and high DPG groups. However, TPG, and in particular PVR, did discriminate survivors from nonsurvivors. The large number of patients with a negative DPG (assuming the negative DPG is the result of measurement error) could bias the results, as the actual DPG may have been elevated in these patients. If this limitation is true then this may speak to a real-world limitation to the use of DPG because these measurements were performed by heart failure cardiologists with significant experience in hemodynamic evaluations. It also remains possible that a very high DPG similar to those seen in idiopathic pulmonary artery hypertension (∼20 mm Hg) (25) could predict survival. Nevertheless, those patients are quite rare in PH-LHD (in this analysis only 9 patients had a DPG>15 mm Hg and only 4 had a DPG >20 mm Hg). PVR and TPG might have influenced the decision of who was ultimately transplanted. In accordance with previous investigations on this topic, we censored participants who went on to require transplantation (n = 36) at the time of transplantation. Censoring participants at the time of transplant could lead to an underestimation of mortality. Furthermore, information regarding medical therapies, echocardiography, and other comorbid conditions such as COPD, smoking, sleep apnea, atrial fibrillation, and renal failure was not available and therefore their association with PH-LHD and survival could not be assessed. In addition, our analysis did not correct for multiple comparisons. Finally, hemodynamic data on response to vasodilators to evaluate the reversibility of PH was not routinely tested in this cohort.
Our study shows that in a large cohort of patients with PH due to left heart disease, including those with out-of-proportion (elevated TPG and PVR) PH, the DPG did not discriminate survivors from nonsurvivors. Considering the technical limitations interfering with the accurate measurement of DPG and other clinical factors that affect the DPG aside from pulmonary vasculature remodeling, this work argues against the use of DPG as a marker of prognosis in patients with PH-LHD. Likewise, the routine use of DPG in diagnostic algorithms of PH-LHD is premature and requires further validation.
All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- combined post-capillary and pre-capillary pulmonary hypertension
- diastolic pulmonary artery pressure
- diastolic pulmonary gradient
- hazard ratio
- mean pulmonary artery pressure
- pulmonary capillary wedge pressure
- pulmonary hypertension
- pulmonary hypertension due to left heart disease
- pulmonary vascular resistance
- transpulmonary gradient
- Received May 15, 2014.
- Revision received July 8, 2014.
- Accepted July 28, 2014.
- 2015 American College of Cardiology Foundation
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