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ORIGINAL ARTICLE
Year : 2022 | Volume
: 11
| Issue : 1 | Page : 20-28
The prognostic significance of the discordance between right- and left-side filling pressures in advanced heart failure: Data from the right heart catheterization registry of rajaie heart center (RHC-RHC Registry)
Sepideh Jafari Naeini1, Ermia Tabandeh2, Sepideh Taghavi2, Ahmad Amin2, Marzieh Mirtajaddini2, Razieh Omidvar2, Majid Maleki2, Hooman Bakhshandeh2, Nasim Naderi2
1 Cardiovascular Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Rajaie Cardiovascular Medical and Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
Correspondence Address:
Prof. Nasim Naderi
Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Valiasr Ave, Hashemi Rafsanjani Blvd, Tehran
Iran
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/rcm.rcm_56_21
Introduction: The prognostic significance of filling pressures and the relationship between left and right heart filling pressures have been well characterized in patients with heart failure. In the present study, we sought to evaluate the prevalence of discordance between left- and right-sided filling pressures and their relationship with clinical characteristics, laboratory data, and outcome measures (mortality and heart transplantation) in patients who were registered in right heart catheterization registry of Rajaie Heart Center (RHC-RHC registry). Methods: The hospital information system was queried for all adult patients with diagnosis of chronic heart failure who had undergone right heart catheterization between July 2009 and July 2019 in heart failure and transplantation department. The following variables were measured for each patient: mean right atrial pressure; systolic and end-diastolic right ventricular pressures; systolic, diastolic, and mean pulmonary artery pressure; pulmonary capillary wedge pressure (PCWP); mixed venous oxygen saturation; and cardiac output and cardiac index by Fick technique. The RAP/PCWP ratio was also calculated. The outcome of interest was all-cause mortality and heart transplantation after the index right heart catheterization. All of the patients were monitored for all-cause mortality or heart transplantation until July 2020. Results: Among 1941 patients, a total of 1078 patients (75% male) were selected. The mean (standard deviation) of age was 42.7 (15.7) years. Heart failure reduced ejection fraction (HFREF) was found in the majority of patients (85.1%), with nonischemic dilated cardiomyopathy and ischemic cardiomyopathy being the most frequent etiologies. The concordance between right and left filling pressures is more noticeable in patients with HFREF and heart failure mildly reduced EF than in patients with heart failure preserved EF (HFPEF). The median (interquartile range) of follow-up duration was 24 (6–48) months. During the follow-up time, 676 (62.7%) patients met the study outcomes of interest within <5 days to 96 months following the index RHC. Conclusion: The results of this study show that right and left filling pressure may be discordant in up to one-third of patients with advanced heart failure. However, the right and left heart-filling pressures would be more concordance as the disease is more advanced.
Keywords: Heart failure, hemodynamics, outcome, right heart catheterization
The prognostic significance of filling pressures and the relationship between left and right heart filling pressures have been well characterized in patients with heart failure.[1] Although right atrial (RA) and pulmonary capillary wedge (PCW) pressure correlate moderately well in patients with heart failure, right- and left-sided filling pressures may be discordant in up to 30%.[2],[3] A simple method for evaluation of filling pressures is the estimation of jugular venous pressure (JVP) by physical examination, however, its value in estimating left-sided filling pressures is limited, particularly in the case of discordance between right and left heart pressures; furthermore improper estimation of left-sided filling pressures may result in over- or undertreatment of congestion.[4],[5] A study done by Campbell et al. shows that over 70% of patients with chronic HF evaluated for heart transplantation demonstrate the concordance of right- and left-sided filling pressures.[2] However, a sizable number of those with elevated filling pressures on either side, have high left or high right mismatch. It is very important, therefore, to recognize the presence of discordance between left- and right-sided filling pressures in patients with heart failure. Several factors such as etiology of heart failure, duration of the disease, presence of concomitant valvular or pulmonary disorders as well as severity of right ventricular (RV) dysfunction may cause discordance between right- and left-side filling pressures.[3],[6],[7],[8],[9]
The relationship between the right and left heart filling pressures can also be expressed as the ratio between the RAP and PCW pressure (PCWP) (RAP/PCWP ratio). This ratio is associated with mortality, heart failure decompensation, and cardiorenal syndrome. Furthermore, this ratio is relatively stable in heart failure patients undergoing hemodynamic-guided therapy, despite treatment with vasoactive drugs and diuretics. It is also considered as a predictor of survival in patients with pulmonary hypertension.[10],[11],[12],[13]
In the present study, we sought to evaluate the prevalence of discordance between left- and right-sided filling pressures and the RAP/PCWP ratio and their relationship with clinical characteristics, laboratory data, and outcome measures (mortality and heart transplantation) in patients with advanced heart failure scheduled for hemodynamic study by right heart catheterization.
MethodsRight heart catheterization registry of Rajaie Heart Center (RHC-RHC registry) is a single-center registry in Rajaie Cardiovascular Medical and Research Center (RCMC), a national referral center and one of the largest heart centers in the Islamic Republic of Iran and in the Middle East for cardiovascular disease located in Tehran/Iran. The RHC-RHC registry was established in July 2009 and is still active until the present day. The data of all the right heart catheterizations have been registered in dedicated RHC-RHC registry forms in hospital information system (HIS).
Patient selection
We retrospectively assessed the chronic heart failure patients referred for right heart catheterization to our center, a tertiary center for heart failure programs. The HIS was queried for all adult patients with diagnosis of chronic heart failure who had undergone right heart catheterization between July 2009-July 2019 in heart failure and transplantation department of RCMC, Tehran/Iran. The following inclusion criteria were used to include the patients:
Right heart catheterization for the first timeThe patients with advanced heart failure regardless of LVEF scheduled for pretransplant evaluation (with an Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS] profile of 3–7)Patients with advanced heart failure scheduled for hemodynamic study in acute heart failure setting due to refractory heart failure symptoms including RV failure or cardiorenal syndromes for decision making about starting inotropes or adjusting the diuretic dose.Patients with a diagnosis of pulmonary arterial hypertension, cardiogenic shock, INTERMACS profile of 1 and 2, acute coronary syndrome, constrictive pericarditis, post heart transplant, end-stage renal diseases (with a history of dialysis), and those with considerable missing data and missed follow-up were excluded.
Advanced heart failure and INTERMACS profile were defined according to the European heart failure guideline.[14] The demographic data, clinical characteristics, and laboratory variables were all obtained from HIS and patients' hospital documents.
The study was approved by the research and ethics committee of our center with the ethical code of IR.IUMS.FMD.REC.1398.401.
Right heart catheterization
All patients were assessed in the catheterization laboratory at rest in supine position while breathing room air using 7F balloon-tipped, triple lumen thermodilution catheters (Edwards Life Sciences, Irvine, CA, USA) or multipurpose A1 catheter. The pressures were all averaged in 3 consecutive heartbeats at end-expiration. The following variables were measured for each patient: mean RA pressure; systolic and end-diastolic RV pressures; systolic, diastolic, and mean PAP; PCWP; mixed venous oxygen saturation; and cardiac output (CO) by Fick technique. The cardiac index was measured by dividing the CO by the body surface area.
According to the Campbell et al. study, the patients were divided into four hemodynamic profiles:[2]
Low match group; RAP <10 and PCWP <22 mmHgHigh match group; RAP ≥10 and PCWP ≥22 mmHgHigh right mismatch group; RAP ≥10 and PCWP <22 mmHgHigh left mismatch group; RAP <10 and PCWP ≥22 mmHg.The RAP/PCWP ratio was also calculated in all study populations.
Outcome measures
The outcome of interest was all-cause mortality and heart transplantation after the index right heart catheterization. All of the patients were monitored for all-cause mortality or heart transplantation until July 2020 by reviewing the hospital records, electronic heart transplant listing registry of the Iran Ministry of health as well as by contacting them on the phone.
Statistical analysis
All analyses were conducted using IBM SPSS statistics 19 for Windows (IBM SPSS Statistics for Windows, Version 19.0. Armonk, NY: IBM Corp. NY, USA). One sample Kolmogorov Smirnov test was used to assess the normal distribution of variables.
Continuous variables with and without normal distribution are presented as means (standard deviation [SD]) and median (interquartile range [IQR]), respectively, and were compared using the Student's t-test, the Mann–Whitney U-test, analysis of variance, and the Kruskal–Wallis test, as appropriate. Categorical data are presented as numbers and percentages and were compared by the Chi-square test. Binary regression multivariable analysis was used for multivariable analysis. Kaplan Meier estimator was used to show the survival of the study population during the follow-up time. The follow-up was ended when the patient met the outcome of interest. All reported probability values were two-tailed, and a P < 0.05 was considered statistically significant.
The study population was divided into three categories according to the European heart failure guideline.[14],[15] including heart failure reduced ejection fraction (HFREF), heart failure preserved EF (HFPEF), and heart failure mildly reduced (mid-range) EF (HFMREF). Tertiles of RA/PCWP ratio were also defined and the study endpoints were examined in each heart failure category and the tertiles.
ResultsAmong 1941 patients scheduled for RHC between July 2009 and July 2019, in our center, a total of 1078 patients (75% male) were selected according to the inclusion criteria. [Figure 1] shows the various diagnoses for all patients who underwent RHC.
Figure 1: Frequency of different diagnoses of all patients undergone hemodynamic study by right heart catheterization (n = 1941)The first results regarding the patients with pulmonary hypertension and the different aspects of patients listed for heart transplantation have been reported elsewhere.[16],[17]
The mean (SD) of age was 42.7 (15.7) between 12 and 85 years.
HFREF was found in the majority of patients (85.1%), with nonischemic dilated cardiomyopathy and ischemic cardiomyopathy (ICMP) being the most frequent etiologies.
Seventy-seven (7.1%) patients were diagnosed as HFPEF and 83 (7.6%) patients were HFMREF.
The most common etiology in both HFPEF and HFMREF was restrictive cardiomyopathy (RCM), 56.3% and 39.1%, respectively. Other etiologies for HFPEF included ischemic heart disease, hypertrophic cardiomyopathy, valvular heart disease, and arrhythmogenic cardiomyopathy (AVC).
ICMP, valvular cardiomyopathy with significant RV failure, and AVC were the other etiologies in patients with HFMREF. [Table 1] shows the demographic, clinical, and laboratory findings of the study population, and [Table 2] shows the RHC data of the study population.
Table 1: Demographic and laboratory findings of study population (n=1078)The median (IQR) of left ventricular ejection fraction (LVEF) in HFREF, HFPEF, and HFMREF was 15% (12.5–20), 55% (50–59.2), and 45% (40–47), respectively.
Thirty percent of RHCs were performed for hemodynamic study in already admitted patients who were not categorized as the INTERMACS class of 1 or 2. The reason for RHC in this group of patients was included deterioration of clinical condition or refractory heart failure symptoms including RV failure or cardiorenal syndromes for decision making about starting inotropes or adjusting the diuretics dose or other treatments for advanced heart failure including heart transplantation or assist device implantation.
In patients who had undergone RHC for pretransplant assessment, the INTERMACS profile was in class 3 and 4 in 182 (24.1%) and 371 (49.2%), respectively, while the remainder were in class 5–7.
For all selected patients, guideline-directed medical therapy and advanced heart failure care program had been optimized and started at the time of hospitalization for RHC.
Hemodynamic data and determination of matched and mismatched categories
[Table 2] shows the hemodynamic data in each category of heart failure. [Figure 2] shows the frequency of each hemodynamic category in subgroups of the study population.
Figure 2: Frequency of each hemodynamic profile subgroup of study population (n = 1078)In those with HFPEF and HFMREF, the most common hemodynamic profile was high right mismatch and high match, respectively. The high left mismatch profile was absent among patients with HFPEF and HFMREF.
The RA/PCWP ratio was significantly higher in the HFMREF group than HFREF and/or HFPEF (P = 0.001).
Tertiles of RA/PCWP ratio were defined as <0.444 (tertile 1); 0.44–0.625 (tertile 2) and >0.625 (tertile 3).
Outcome measures in all study groups
The median (IQR) of follow-up duration was 24 (6–48) months. During the follow-up time, 676 (62.7%) patients met the study outcomes of interest within less than 5 days to 96 months following the index RHC. The mortality and heart transplantation rate in our study population was about 52% and 10.8%, respectively. Among 1078 patients who have undergone RHC between 2009 and 2019, 560 patients died and 116 were transplanted until July 2020.
In patients with HFPEF and HFMREF, 49 (64%), and 27 (32%) died, respectively, and the median survival for each HFPEF and HFMREF was 12 (9–55) and 36 (18–48) months, respectively.
During the follow-up period, no HFPEF patients and only two HFMREF patients were transplanted.
Study results in heart failure with reduced ejection fraction
As the HFREF patients comprised most of the study population, here we are going to present more detail about this group. [Table 3] shows the demographic, clinical, and laboratory data of HFREF patients.
Table 3: Demographic, laboratory, and right heart catheterization findings of patients with heart failure reduced ejection fraction (n=918)A total of 918 patients (78.5% male) were enrolled as HFREF (LVEF <40%) in this study. [Table 4] depicts comparing demographic and clinical characteristic of this group considering the four hemodynamic profiles. After RHC, GDMT was started or optimized for all of them and about 95% of these patients had regular outpatient follow-ups. Almost all patients who visited the heart failure department's outpatient clinic and/or infusion unit on a regular basis were prescribed guideline-directed medical therapies based on their tolerance and the presence of contraindications such as hyperkalemia, renal dysfunction, or recurrent hypotensive episodes.
Table 4: Comparing demographic and clinical characteristics of patients with heart failure reduced ejection fraction in four hemodynamic profiles (n=918)The median (IQR) LVEF was 15% (12.5–20), and the mean (SD) age of this group was 40.7 (15) years between 13 and 85 years. The most common hemodynamic profile in this group was high match group (52.9%). The mean (SD) of RAP for patients with PCWP ≥22 mmHg was 16.4 (7.3) mmHg and the mean (SD) of PCWP for patients with RAP ≥10 mmHg was 28.6 (8.6) mmHg.
As shown in [Table 4], patients in high match profile had higher Pro BNP, BUN, creatinine, and uric acid and lower serum sodium level (P < 0.005).
Outcome measures in heart failure reduced ejection fraction group
[Figure 3] shows the frequency of the all-cause mortality in different hemodynamic subgroups in heart failure reduced ejection fraction patients. During the follow-up time with a median (IQR) of 24 (6–48) months, the all-cause mortality and transplantation rate in the HFREF group were 52% and 12.4%, respectively. The rate of heart transplantation in HFREF patients who were listed was about 40%. The median (IQR) of survival without heart transplant in this group was 24 (6–48) months. The median time between RHC and heart transplant was 3 (1.25–9) months (IQR), ranging from 6 days to 3 years.
Figure 3: The frequency of the all-cause mortality in different hemodynamic subgroups in heart failure reduced ejection fraction patientsIt should be noted that heart transplantation began at our center in 2008, and the number of transplants has risen since 2014. However, as previously stated in this study, data on the destiny of the heart transplantation waiting list has been presented in detail in another paper.
[Figure 4] depicts the Kaplan Mayer's survival curve in 4 hemodynamic profiles. The survival rate was significantly reduced in patients with high match profile, and the high right mismatch group was placed in the second position in this regard.
Figure 4: Kaplan–Meier curve of survival analysis in four hemodynamic profiles of patients with heart failure reduced ejection fraction (n = 918)[Figure 5] shows the comparison of mortality rate among the three tertiles of RA/PCWP ratio. As shown in this figure, mortality rate is significantly higher in tertile 2 and 3 (P < 0.0001).
Figure 5: Mortality rate in three tertiles of right atrial to pulmonary capillary wedge pressure ratio in patients with heart failure reduced ejection fraction (n = 918)[Table 5] shows the predictors of death in this group of patients. Although the hemodynamic measures and profile would have an association with mortality in univariable analyses, binary logistic multivariable analysis revealed that the cardiac index, RA/PCWP ratio, serum creatinine, and NT pro BNP level could be considered as independent predictors of mortality in HFREF patients, as shown in this table.
Table 5: Predictors of mortality in patients with heart failure reduced ejection fraction in univariate and binary logistic multivariable analyses (n=918) Discussion The current study represents the destiny of a large number of advanced heart failure patients who have undergone RHC with various indications. Hemodynamics is the most important predictor of mortality and hospitalization in patients with heart failure regardless of their LVEF.[1],[6],[18],[19],[20] Careful assessment of hemodynamic status and planning for appropriate therapeutic management based on it can reduce the rate of symptoms as well as hospital admissions and mortality. Considering the limitations in precise estimation of hemodynamics by noninvasive methods and physical examination, right heart catheterization is still the gold standard tool for the assessment of intracardiac pressures, estimation of the prognosis, and making therapeutic decisions.[1],[4],[5],[6],[18],[19],[20],[21]
Aside from the pressure values obtained by RHC, researchers tried to establish innovative measures utilizing catheterization data and assessing their prognostic value as well as their association with noninvasive measures in various clinical settings.[1],[2],[6],[10]
In this report, we aimed to show the prognostic significance of the discordance between right- and left-side filling pressures in advanced heart failure. Furthermore, we assessed the RAP/PCWP ratio as an index of right heart function and its clinical significance in each group of the hemodynamic profiles.
Our findings demonstrate that the majority of our study participants have a decreased ejection fraction (HFREF), with pre-transplant evaluation being the most common reason for RHC.
Apparently, the hemodynamic profile would be dependent on the etiology of heart failure as well as the demographic and clinical characteristics of the study population. However, our findings are strikingly comparable to those of earlier studies. The concordance between right and left filling pressures is more noticeable in patients with HFREF and HFMREF than in patients with HFPEF, according to the analysis of hemodynamic profiles in different subgroups of these patients regardless of LVEF [Figure 2].
In studies done by Drazner et al. and Campbell et al., right and left filling pressures were matched in more than 70% of different subgroups of heart failure patients with HFREF. Furthermore, HFPEF patients had dominant high-R mismatch in Drazner et al. and Horiuchi et al. studies.[2],[8],[9],[22]
Although a small sample size could be the reason of a lower number of patients with high left mismatch profile in the HFMREF and HFPEF groups, the findings would point to higher prevalence of right heart dysfunction in these two groups of heart failure patients.
An Increased RAP/PCWP ratio despite a lower PVR in the HFMREF group shows that this group of patients has significantly reduced right heart performance. RCM was the most common etiology of heart failure in the HFMREF group, so more severe right heart dysfunction despite a lower PVR would be better explained by a more severe pathologic involvement of myocardial tissue and significant RV diastolic dysfunction. The lower PVR in HFMREF can also be due to a higher CO in these patients which makes the role of impaired relaxation of right-sided myocardium in pathophysiology of their disturbed cardiac performance more pronounced.
The higher prevalence of high match profile in HFREF patients indicates higher referral of more advanced patients to a heart failure tertiary center like our hospital.
Prognostic significance of hemodynamic profiles
The rate of all-cause mortality was about 52% over the follow-up time, which is compatible with the previous reports regarding patients with advanced heart failure.
Specifically, the statistical analyses in the HFREF group showed a higher all-cause mortality in those with high match profile. Furthermore, the high match group had worse renal function, lower serum sodium level, higher NT-Pro BNP, and a higher serum uric acid level. The prognostic role of these factors has previously been shown.[23],[24],[25]
Presence of comorbidities, high PVR, limited donor pool, and limitations in providing long-term ventricular assist devices are the most common reasons of high mortality rate in advanced HFREF patients particularly high match group despite guideline-directed therapies.
Among different hemodynamic predictors of mortality including the hemodynamic profile, the RA/PCWP ratio was independently associated with mortality in HFREF patients [Table 5].
Many investigations have shown a higher predictive value of RA/PCWP ratio than RA or PCWP alone in prediction of hospitalization, renal failure, post-heart surgery RV failure, and mortality in patients with heart failure and pulmonary hypertension regardless of the etiology.[9],[10],[11],[13]
Study limitations
The current study is a registry-based cohort. We had no hypothesis before the investigation and relied on post hoc analysis to discover the correlations. The large number of study population would be the strength of the study; however, although we tried to do our best to address them, the registry-based study limitations could be considered for this study such as the limited availability of patients' treatment data overtime, under-reporting the outcome measures and missed follow-ups.
ConclusionThe results of this study show that right and left filling pressure may be discordant in up to one-third of patients with advanced heart failure. So, in around 30% of these patients, noninvasive estimation of left heart filling pressure using the JVP or central vein pressure may be misleading, and conducting RHC may be beneficial if there is any suspicion in the estimation of filling pressures. However, the right and left heart-filling pressures would be more concordance as the disease is more advanced.
Ethical clearance
The study was approved by the research and ethics committee of our center with the ethical code of IR.IUMS.FMD. REC.1398.401.
Acknowledgments
We would like to thank our colleagues in Rajaie Cardiovascular Medical and Research Center for helping us to perform this study in particular Dr. Yousef Moghaddam, Mr. Peyman Tabatabaei, and Mrs. Hengameh Meschi. We would also like to thank Dr. Nick Austin for the language editing the manuscript.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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