- Email: [email protected]
Right-Sided Cardiac Dysfunction in Heart Failure With Preserved Ejection Fraction and Worsening Renal Function
Accepted Manuscript Right Sided Heart Dysfunction In Heart Failure With Preserved Ejection Fraction And Worsening Renal Function Monica Mukherjee, MD, MPH, Kavita Sharma, MD, Jose A. Madrazo, MD, Ryan J. Tedford, MD, Stuart D. Russell, MD, Allison G. Hays, MD PII:
S0002-9149(17)30707-5
DOI:
10.1016/j.amjcard.2017.04.019
Reference:
AJC 22575
To appear in:
The American Journal of Cardiology
Received Date: 28 January 2017 Revised Date:
26 March 2017
Accepted Date: 12 April 2017
Please cite this article as: Mukherjee M, Sharma K, Madrazo JA, Tedford RJ, Russell SD, Hays AG, Right Sided Heart Dysfunction In Heart Failure With Preserved Ejection Fraction And Worsening Renal Function, The American Journal of Cardiology (2017), doi: 10.1016/j.amjcard.2017.04.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Mukherjee et al. 1
Right Sided Heart Dysfunction In Heart Failure With Preserved Ejection Fraction And Worsening Renal Function
MD; Stuart D. Russell, MD; Allison G. Hays, MD
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Monica Mukherjee, MD, MPH; Kavita Sharma, MD; Jose A. Madrazo, MD, Ryan J. Tedford,
The Johns Hopkins University Division of Cardiology, Baltimore, MD 21224
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RUNNING TITLE
ACADEMIC AFFILIATION
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Right Heart Dysfunction In Heart Failure With Preserved Ejection Fraction With Renal Failure
All authors are affiliated with Johns Hopkins University School of Medicine, Division of
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Cardiology, Baltimore, MD 21224
CORRESPONDING AUTHOR Monica Mukherjee, MD, MPH
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301 Mason Lord Drive, Suite 2400 Baltimore, MD 21224
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Phone: 410-550-1120 Fax: 410-550-1183
Email: [email protected]
ACCEPTED MANUSCRIPT Mukherjee et al. 2
ABSTRACT In urban populations, worsening renal function (WRF) is well-established in patients hospitalized with acute decompensated heart failure with preserved ejection fraction (HFpEF). However, the
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mechanisms for development of WRF in the setting of acute heart failure in HFpEF are unclear. In the present study, we sought to characterize conventional echocardiographic measures of right ventricular (RV) chamber size and function to determine whether RV dysfunction and/or adverse
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RV remodeling is related to WRF in HFpEF patients. Our study included 104 adult HFpEF patients (EF≥55%) with technically adequate 2D echocardiograms performed during their
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hospitalization for acute decompensated heart failure to determine echocardiographic predictors of WRF, defined as a serum Creatinine (Cr) increase of ≥ 0.3 mg/dl within 72 hours of hospitalization. Thirty-eight (36%) of the 104 patients developed WRF (mean Cr increase=0.9± 0.1 mg/dl) during the hospitalization (mean age ± SD of 64 ± 12 years, 27 women (71%), 29
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Black (76%)). There were no significant differences in LV medial E/e’ ratio and RV systolic pressure by WRF status, or in linear dimensions of RV and right atrial (RA) size. RV fractional area change, a measure of RV function, however, was significantly decreased in HFpEF patients
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with WRF compared to the no WRF group (p=0.003) while RV free wall thickness (p=0.001) was increased. In conclusion, linear and volumetric measures of dimensions of RA and RV
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chamber size did not distinguish HFpEF patients with and without WRF. However, in HFpEF patients with WRF during acute heart failure hospitalization, there was a significant decrease in RV function and a significant increase in RV free wall thickness compared to matched patients with no WRF. These findings suggest that adverse RV remodeling and RV dysfunction occur in HFpEF patients with WRF.
ACCEPTED MANUSCRIPT Mukherjee et al. 3
KEYWORDS: right ventricle, renal failure, heart failure with preserved ejection fraction, echocardiography
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INTRODUCTION Prior studies have shown that right ventricular (RV) dysfunction is common in both HFrEF (heart failure with reduced ejection fraction) and HFpEF (heart failure with preserved ejection fraction) and is associated with high mortality, morbidity, and hospital readmission
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rates.1-4 In HFpEF, elevated left and right sided filling pressures predominate from normal, and
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these factors may contribute to increased central venous pressure that is associated with impaired renal function,5 although this has not been systematically evaluated in the acute heart failure setting. Worsening renal function (WRF) occurs commonly in HFpEF patients6 and is related to poor clinical outcomes5,7-9. However, it is unknown whether RV dysfunction contributes to WRF in the acute heart failure setting.
Therefore, to better understand the underlying
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mechanisms of WRF in this population, we aimed to test the hypothesis that subclinical RV dysfunction may be related to WRF in HFpEF patients from a racially diverse urban cohort. In the present study, we assessed echocardiographic measures of RV structure and function to
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determine whether RV dysfunction and adverse RV remodeling are related to WRF in HFpEF
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patients hospitalized for acute heart failure.
METHODS
Following approval by the Institutional Review Board at Johns Hopkins University School of Medicine, patients hospitalized for acute decompensated heart failure at the Johns Hopkins Hospital from July 2011 to June 2012 were identified by the primary discharge
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diagnosis code 428 according to the International Classification of Diseases, Ninth Revision, Clinical Modification.8 Of these patients, records of those with left ventricular ejection fraction measurement of ≥55% during their hospitalization. If a patient was admitted for heart failure on
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more than one occasion during the study period, only data from the first admission was included for analysis. The diagnosis of heart failure was confirmed by Framingham criteria.10
Patients with the following features were excluded from analysis: active ischemic heart
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disease (e.g., acute coronary syndrome or symptoms of angina), severe valvular dysfunction,
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primary cardiomyopathy (e.g., active myocarditis, hypertrophic obstructive cardiomyopathy, constrictive or restrictive (including known amyloidosis, sarcoidosis, or hemochromatosis), complex congenital heart disease, or severe primary pulmonary hypertension. End-stage renal disease was defined as requiring dialysis, or with estimated glomerular filtration rate (eGFR) ≤15 ml/min/1.73 m2, determined by the Chronic Kidney Disease Epidemiology Collaboration
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equation.11 Chronic kidney disease (CKD) was defined as eGFR <60 ml/min/1.73 m2 at initial presentation. WRF was defined as an increase in serum Creatinine by ≥ 0.3 mg/dl from admission to within the first 72 hours of hospitalization.12 Hospital readmission data were
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acquired through review of the Johns Hopkins Hospital and Johns Hopkins Bayview Medical
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Center electronic medical record systems. All patients included in the study underwent clinically indicated echocardiograms during
index. Echocardiograms were performed at a single clinical site using Phillips ie33 ultrasound machine (Phillips Healthcare, Andover, MA) with subjects in the left lateral decubitus position. 2D-directed methods were used to obtain linear measurements of RV chamber size in accordance with American Society of Echocardiography (ASE) guidelines.13 Right atrial size (RA) was estimated using area from the apical 4-chamber view calculated by Simpson’s biplane method of
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discs from the apical 4-chamber view in atrial end-diastole. In accordance with ASE Guidelines, a formula of RV end-diastole area minus RV end-systole area and divided by RV end-diastolic area was used to calculate RV fractional area change (FAC, %).13 Abnormal RV function was
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defined as FAC < 35%. Tricuspid annular systolic plane excursion (TAPSE) and tissue Doppler derived S' systolic velocity were not utilized as surrogates for RV function given lack of consistent availability on clinical echocardiograms performed during our study period. Right
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ventricular systolic pressure (RVSP) was estimated using established methods.14 RVSP of ≥ 36 mmHg was identified as abnormal in accordance with ASE guidelines.15 RV wall thickness was
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measured from the 2D echocardiographic subcostal image plane in end-diastole at the level of the tip of the anterior tricuspid valve leaflet. RV wall thickness of ≥ 5.0 mm was defined as abnormal.13 Left ventricular diastolic parameters including mitral inflow with early diastolic (E) and late diastolic (A) velocities, and tissue Doppler medial e’ velocities that were obtained by
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convention in the absence of significant mitral annular calcification, mitral prostheses, atrial fibrillation, and/or mitral stenosis.16 The ratio of the early transmitral flow velocity (E) to medial e’ (E/e’) were used to estimate LV filling pressure. Board-certified echocardiologists were
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blinded to clinical variables during echocardiographic interpretation. Statistical analyses were performed using STATA version 13.0 (College Station, TX,
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USA). Baseline characteristics and echocardiography parameters are expressed as mean values ± one standard error of the mean. Shapiro-Wilk test was used to assess normality of the data. Differences in continuous variables and dichotomous/categorical variables were examined using a Student’s t test or a χ2 square test, respectively. Linear regression analysis was performed to assess
the
relationship
between
continuous
variables
anthropomorphic
data
and
echocardiographic parameters in HFpEF patients with WRF and no WRF. Pearson’s Correlation
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was employed to ascertain the relationship between heart failure outcomes, echocardiographic and demographic. Statistical significance was defined as a two-tailed p-value ≤ 0.05.
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RESULTS
All data is presented as mean ± standard deviation. Of 434 patients hospitalized for heart failure during the study period, 206 patients (47%) met the predefined criteria for HFpEF. The
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final study population consisted of 104 HFpEF patients with technically adequate echocardiograms during their hospitalization to allow for comprehensive right-sided cardiac
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analysis by echocardiogram. The majority of our 104 patients were women (62%), Black (70%) with a mean age of 62 ± 13 years and New York Heart Association (NYHA)8 Class II symptoms of heart failure on admission. The majority of patients were hypertensive (84%), with high rates of metabolic syndrome (62%) and diabetes mellitus (57%). Additional demographic and clinical
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characteristics of participants are presented in Table 1.
During the index hospitalization for volume overload in this HFpEF cohort, admission blood pressure was 148 ± 34 / 75 ± 17 mmHg with mean admission creatinine (Cr) of 1.6 ± 1.2
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mg/dl. WRF, defined as an increase in serum Cr by ≥ 0.3 mg/dl within the first 72 hours of hospitalization, occurred in 38 of the 104 patients (37%). Age, gender, race, and co-morbid
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conditions were not predictors of WRF, similar to prior observations.6 β-naturetic peptide was not routinely available for analysis. Average length of hospital stay was 8 ± 12 days. There was a mean net fluid loss of 6 ± 9 liters throughout their hospital stay, with net weight loss of 5 ± 10 pounds. Eleven of the 104 patients (11%) were rehospitalized within 30 days of discharge for recurrent heart failure, and 8 (8%) were hospitalized for non-heart failure admissions. There was a 14% 1-year mortality rate overall.
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All 104 HFpEF patients had normal left ventricular systolic function by inclusion criteria, with normal LV cavity size and mild to moderate left ventricular hypertrophy as shown in Table 2. Mitral inflow pattern ratio of early (E) and late (A) diastolic velocities were suggestive of
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Grade 1 diastolic dysfunction, with elevated LV filling pressures (septal E/e’=15.4 ± 7.4). Mean tissue Doppler derived medial e’velocity was reduced at 7.3 ± 2.7 cm/s. RA area (RAA) was elevated, as was linear dimension of the RV base. Mean RV fractional area change was 44.7 ±
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0.1 % and RVSP was elevated (49.4 ± 18 mmHg). The prevalence of abnormal RV FAC, defined by ASE cuttoff of <35%,15 was 9% in our HFpEF cohort. Fifty-five of the 104 patients (53%)
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had pulmonary hypertension, defined as RVSP ≥ 35 mmHg, with an average RVSP of 52 ± 14 mmHg in this subgroup.
Echocardiographic parameters of HFpEF patients were analyzed according to WRF status, demonstrated in Table 3. There was no significant difference in mean RV basal diameter
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between groups or RA area. However, RV wall thickness was significantly increased in HFpEF patients with WRF compared to those without WRF (p= 0.001). In terms of RV functional parameters, RV FAC (fractional area change, reflective of RV function) was significantly lower
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in the WRF group compared to the no WRF group, Table 3 With regards to hemodynamic parameters and diastolic assessment, E/A ratio was not
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significantly different between groups (p=0.49). There were no significant differences in either LV medial E/e’ ratio or RVSP (Table 3). Finally, estimated RA pressure (RAP) was higher in the WRF group compared to the no WRF group approaching statistical significance.
DISCUSSION
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In the present study of a diverse, urban cohort of HFpEF patients, detailed echocardiographic analysis of right sided structural and hemodynamic parameters revealed that RV dysfunction, reflected by reduced RV FAC was significantly related to WRF in patients
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admitted for heart failure. WRF during inpatient hospitalization has been shown to portend poor mortality and morbidities outcomes in heart failure, with most studies focusing on heart failure with reduced ejection fraction.12,17 Sharma et al described a higher rate of WRF during
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hospitalization for decompensated HFpEF in an urban HFpEF population than previously reported in other cohorts.6 In the present study, we focused on a subset of HFpEF patients with
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technically adequate 2D echocardiograms allowing comprehensive RV analysis, the majority of which were performed during the index hospitalization for heart failure. Our HFpEF cohort had baseline renal dysfunction as evidenced by elevation in mean admission Cr (Table 1). With regards to WRF status, we observed no significant difference in linear dimensions of RV
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chamber size between groups. However, there was a significantly higher RA pressure and lower in RV FAC in the WRF group compared to no WRF group, primarily due to an increase in RV systolic area (Table 3). To our knowledge, this is the first report in a community based HFpEF
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population demonstrating a significant association between RV dysfunction and worsening renal function in the acute heart failure setting. Our findings are of particular importance given the
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diverse nature of our cohort with a large proportion of Black participants, an underrepresented study population with exceedingly high mortality from HFpEF.9 Prior studies in heart failure patients demonstrated that measures of RV dysfunction have
strong predictive value for mortality and heart failure rehospitalizations.18 In the present study, we utilized RV FAC as a surrogate for RVEF, and observed decreased RV FAC in hospitalized HFpEF patients with WRF compared to those without WRF. RV FAC is a quantitative measure
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of RV function that is accurate, reproducible, standardized in imaging guidelines,15 and used extensively in the heart failure literature.1,3,19 Our study reported an overall prevalence of abnormal RV FAC (defined by ASE cuttoff of <35%) of 9% overall, comparable to prior
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reports.20 To our knowledge, this is the first study to demonstrate reduced RV FAC by WRF status, suggestive of impaired RV function in this group of hospitalized HFpEF patients. RV function and contractile reserve was previously shown to be a predictor of functional capacity
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and mortality in patients with pulmonary hypertension (PH), and more recently in HFpEF.21-23 However, in the present study, we observed RV dysfunction despite no significant group
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differences in LV medial E/e’ ratio and RVSP, suggesting that findings of diminished FAC were not solely due to elevation in filling pressures in decompensated heart failure. These findings may be explained by differences in pulmonary vascular resistance between groups, although this was not specifically assessed in the current study. Taken together, the RV dysfunction observed
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in this study may be mutifactorial and merits further investigation in larger populations. Patients in the WRF group had increased RV free wall thickness compared to the no WRF group, suggestive of some degree of chronicity of RV dysfunction and remodeling,
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possibly due to an adaptative response to chronic or recurrent elevations in pulmonary pressure. PH associated with HFpEF is more common than previously recognized and is associated with
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hypertension in symptomatic elderly women with impaired GFR.24,25 Although we observed a statistically significant difference in RV wall thickness in WRF compared to no WRF HFpEF patients, the relative difference in wall thickness was small (<1 mm).
Therefore, the
measurement of RV thickness will need to be validated in larger cohort studies to determine clincial utility and prognostic value. The combination of higher RV wall thickness, lower RV FAC and similar estimated RVSP between the WRF and non-WRF groups raises the possibility
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that the WRF group represents a subgroup of patients with more chronic exposure to elevated pulmonary pressures and perhaps a more advanced disease state that is progressing to RV failure.
development of WRF and may portend poor clinical outcomes.
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The characterization of RV dysfunction may help identify HFpEF patients at increased risk for
There were several limitations to the present study. First, the ability to perform comprehensive echocardiographic analysis is largely dependent on 2D image quality, particular
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with regards to detailed analysis of the RV, which can be technically challenging. In addition, our study was limited by its retrospective single-centered nature, where data was abstracted from
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medical records and therefore reliant on adequate reporting and documentation. Finally, while important associations can be made between echocardiographic findings and WRF in HFpEF, our findings cannot be extrapolated as cause and effect.
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DISCLOSURES
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The authors have no conflicts of interest or funding to disclose.
ACCEPTED MANUSCRIPT Mukherjee et al. 11
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16. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF, 3rd, Dokainish H, Edvardsen T, Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK, Alexandru Popescu B, Waggoner AD, Houston T, Oslo N, Phoenix A, Nashville T, Hamilton OC, Uppsala S, Ghent,
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Variable
n=104
Age (years), mean ± SD
62 ± 13
Women
64 (62%)
Race/Ethnicity 73 (70%)
White
30 (29%)
Other
1 (1%)
Body Mass Index (kg/m2)
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Black
39 ± 13
Admission Creatinine (mg/dl) Creatinine at 48 hours Creatinine at 72 hours Creatinine Difference (mg/dl)
1.6 ± 1.2 1.8 ± 1.3 1.8 ± 1.3
0.3 ± 0.4
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Worsening Renal Failure in first 72 hours of 38 (37%) admission 32 (31%)
NYHA Class I
14 (14%)
NYHA Class III
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NYHA Class IV
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Iodinized Contrast During Hospital Admission
NYHA Class II
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TABLE 1: Baseline Clinical Characteristics of Heart Failure With Preserved Ejection Fraction Cohort
47 (45%) 25 (24%) 17 (17%)
Atrial Fibrillation
25 (24%)
Hypertension
87 (84%)
Prior Myocardial Infarction
16 (16%)
Obstructive Sleep Apnea
11 (33%)
Diabetes Mellitus
59 (57%)
Metabolic Syndrome
61 (62%)
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TABLE 2: Baseline Echocardiographic Characteristics of Heart Failure With Preserved Ejection Fraction Cohort n=104
Left Ventricular Ejection Fraction (%)
60 ± 6
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2D Echocardiographic Parameters
Left Ventricular End Diastolic Diameter (cm)
4.6 ± 0.7
Left Ventricular End Systolic Diameter (cm)
3.1 ± 0.7
Interventricular Septum (cm)
1.3 ± 0.3
1.2 ± 0.2
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Posterior Wall (cm)
100 ± 32
Left Atrial Systolic Diameter (cm)
4.1 ± 0.9
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Left Ventricular Mass Indexed to Body Surface Area (g/m2)
Mitral Inflow E/A Septal E/e’ Right Atrial Area
Right Atrial Area index to BSA (ml/m2) Right Ventricular Base
1.33 ± 0.77 15.4 ± 7.4 21 ± 7.1 6.7 ± 5.4 4.1 ± 0.7 18.2 ± 6.2
Right Ventricular Systolic Area (cm2)
10.1 ± 4.1
Fractional Area Change (%)
45 ± 0.1
Right Ventricular Free Wall Thickness (mm)
4.5 ± 0.8
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Right Ventricular Diastolic Area (cm2)
7.7 ± 4.5
Right Ventricular Systolic Pressure (mm Hg)
49 ± 18
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Right Atrial Pressure (mm Hg)
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No WRF
WRF
LV Ejection Fraction (%)
59 ± 6
61 ± 8
0.25
Mitral Inflow E/A
1.37 ± 0.84
1.25 ± 0.63
0.49
LV Septal E/e’
14.3 ± 6.7
17.6 ± 8.2
0.10
Right Atrial Area (cm2)
21 ± 7
21 ± 7
0.71
Right Ventricular Base (cm)
4.1 ± 0.7
4.0 ± 0.5
0.74
Right Atrial Pressure (mmHg)
7 ± 4.6
9±4
0.05
Right Ventricular Systolic Pressure (mmHg)
47.2 ± 16
46.5 ± 15.2
0.87
Right Ventricular Free Wall thickness (mm)
4.3 ± 0.8
4.9 ± 0.8
0.001
Right Ventricular Diastolic Area (cm2)
18.5 ± 6.7
17.6 ± 5.4
0.54
9.9 ± 4.2
10.5 ± 3.9
0.52
40.6 ± 0.1
0.003
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Right Ventricular Systolic Area (cm2)
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Right Ventricular Fractional Area Change (%) 46.9 ± 0.1
p-value
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Echocardiographic Parameters
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TABLE 3: Differences in Echocardiographic Parameters Between Heart Failure With Preserved Ejection Fraction Patients With And Without Renal Failure
S0002-9149(17)30707-5
DOI:
10.1016/j.amjcard.2017.04.019
Reference:
AJC 22575
To appear in:
The American Journal of Cardiology
Received Date: 28 January 2017 Revised Date:
26 March 2017
Accepted Date: 12 April 2017
Please cite this article as: Mukherjee M, Sharma K, Madrazo JA, Tedford RJ, Russell SD, Hays AG, Right Sided Heart Dysfunction In Heart Failure With Preserved Ejection Fraction And Worsening Renal Function, The American Journal of Cardiology (2017), doi: 10.1016/j.amjcard.2017.04.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Mukherjee et al. 1
Right Sided Heart Dysfunction In Heart Failure With Preserved Ejection Fraction And Worsening Renal Function
MD; Stuart D. Russell, MD; Allison G. Hays, MD
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Monica Mukherjee, MD, MPH; Kavita Sharma, MD; Jose A. Madrazo, MD, Ryan J. Tedford,
The Johns Hopkins University Division of Cardiology, Baltimore, MD 21224
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RUNNING TITLE
ACADEMIC AFFILIATION
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Right Heart Dysfunction In Heart Failure With Preserved Ejection Fraction With Renal Failure
All authors are affiliated with Johns Hopkins University School of Medicine, Division of
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Cardiology, Baltimore, MD 21224
CORRESPONDING AUTHOR Monica Mukherjee, MD, MPH
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301 Mason Lord Drive, Suite 2400 Baltimore, MD 21224
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Phone: 410-550-1120 Fax: 410-550-1183
Email: [email protected]
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ABSTRACT In urban populations, worsening renal function (WRF) is well-established in patients hospitalized with acute decompensated heart failure with preserved ejection fraction (HFpEF). However, the
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mechanisms for development of WRF in the setting of acute heart failure in HFpEF are unclear. In the present study, we sought to characterize conventional echocardiographic measures of right ventricular (RV) chamber size and function to determine whether RV dysfunction and/or adverse
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RV remodeling is related to WRF in HFpEF patients. Our study included 104 adult HFpEF patients (EF≥55%) with technically adequate 2D echocardiograms performed during their
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hospitalization for acute decompensated heart failure to determine echocardiographic predictors of WRF, defined as a serum Creatinine (Cr) increase of ≥ 0.3 mg/dl within 72 hours of hospitalization. Thirty-eight (36%) of the 104 patients developed WRF (mean Cr increase=0.9± 0.1 mg/dl) during the hospitalization (mean age ± SD of 64 ± 12 years, 27 women (71%), 29
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Black (76%)). There were no significant differences in LV medial E/e’ ratio and RV systolic pressure by WRF status, or in linear dimensions of RV and right atrial (RA) size. RV fractional area change, a measure of RV function, however, was significantly decreased in HFpEF patients
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with WRF compared to the no WRF group (p=0.003) while RV free wall thickness (p=0.001) was increased. In conclusion, linear and volumetric measures of dimensions of RA and RV
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chamber size did not distinguish HFpEF patients with and without WRF. However, in HFpEF patients with WRF during acute heart failure hospitalization, there was a significant decrease in RV function and a significant increase in RV free wall thickness compared to matched patients with no WRF. These findings suggest that adverse RV remodeling and RV dysfunction occur in HFpEF patients with WRF.
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KEYWORDS: right ventricle, renal failure, heart failure with preserved ejection fraction, echocardiography
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INTRODUCTION Prior studies have shown that right ventricular (RV) dysfunction is common in both HFrEF (heart failure with reduced ejection fraction) and HFpEF (heart failure with preserved ejection fraction) and is associated with high mortality, morbidity, and hospital readmission
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rates.1-4 In HFpEF, elevated left and right sided filling pressures predominate from normal, and
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these factors may contribute to increased central venous pressure that is associated with impaired renal function,5 although this has not been systematically evaluated in the acute heart failure setting. Worsening renal function (WRF) occurs commonly in HFpEF patients6 and is related to poor clinical outcomes5,7-9. However, it is unknown whether RV dysfunction contributes to WRF in the acute heart failure setting.
Therefore, to better understand the underlying
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mechanisms of WRF in this population, we aimed to test the hypothesis that subclinical RV dysfunction may be related to WRF in HFpEF patients from a racially diverse urban cohort. In the present study, we assessed echocardiographic measures of RV structure and function to
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determine whether RV dysfunction and adverse RV remodeling are related to WRF in HFpEF
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patients hospitalized for acute heart failure.
METHODS
Following approval by the Institutional Review Board at Johns Hopkins University School of Medicine, patients hospitalized for acute decompensated heart failure at the Johns Hopkins Hospital from July 2011 to June 2012 were identified by the primary discharge
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diagnosis code 428 according to the International Classification of Diseases, Ninth Revision, Clinical Modification.8 Of these patients, records of those with left ventricular ejection fraction measurement of ≥55% during their hospitalization. If a patient was admitted for heart failure on
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more than one occasion during the study period, only data from the first admission was included for analysis. The diagnosis of heart failure was confirmed by Framingham criteria.10
Patients with the following features were excluded from analysis: active ischemic heart
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disease (e.g., acute coronary syndrome or symptoms of angina), severe valvular dysfunction,
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primary cardiomyopathy (e.g., active myocarditis, hypertrophic obstructive cardiomyopathy, constrictive or restrictive (including known amyloidosis, sarcoidosis, or hemochromatosis), complex congenital heart disease, or severe primary pulmonary hypertension. End-stage renal disease was defined as requiring dialysis, or with estimated glomerular filtration rate (eGFR) ≤15 ml/min/1.73 m2, determined by the Chronic Kidney Disease Epidemiology Collaboration
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equation.11 Chronic kidney disease (CKD) was defined as eGFR <60 ml/min/1.73 m2 at initial presentation. WRF was defined as an increase in serum Creatinine by ≥ 0.3 mg/dl from admission to within the first 72 hours of hospitalization.12 Hospital readmission data were
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acquired through review of the Johns Hopkins Hospital and Johns Hopkins Bayview Medical
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Center electronic medical record systems. All patients included in the study underwent clinically indicated echocardiograms during
index. Echocardiograms were performed at a single clinical site using Phillips ie33 ultrasound machine (Phillips Healthcare, Andover, MA) with subjects in the left lateral decubitus position. 2D-directed methods were used to obtain linear measurements of RV chamber size in accordance with American Society of Echocardiography (ASE) guidelines.13 Right atrial size (RA) was estimated using area from the apical 4-chamber view calculated by Simpson’s biplane method of
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discs from the apical 4-chamber view in atrial end-diastole. In accordance with ASE Guidelines, a formula of RV end-diastole area minus RV end-systole area and divided by RV end-diastolic area was used to calculate RV fractional area change (FAC, %).13 Abnormal RV function was
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defined as FAC < 35%. Tricuspid annular systolic plane excursion (TAPSE) and tissue Doppler derived S' systolic velocity were not utilized as surrogates for RV function given lack of consistent availability on clinical echocardiograms performed during our study period. Right
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ventricular systolic pressure (RVSP) was estimated using established methods.14 RVSP of ≥ 36 mmHg was identified as abnormal in accordance with ASE guidelines.15 RV wall thickness was
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measured from the 2D echocardiographic subcostal image plane in end-diastole at the level of the tip of the anterior tricuspid valve leaflet. RV wall thickness of ≥ 5.0 mm was defined as abnormal.13 Left ventricular diastolic parameters including mitral inflow with early diastolic (E) and late diastolic (A) velocities, and tissue Doppler medial e’ velocities that were obtained by
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convention in the absence of significant mitral annular calcification, mitral prostheses, atrial fibrillation, and/or mitral stenosis.16 The ratio of the early transmitral flow velocity (E) to medial e’ (E/e’) were used to estimate LV filling pressure. Board-certified echocardiologists were
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blinded to clinical variables during echocardiographic interpretation. Statistical analyses were performed using STATA version 13.0 (College Station, TX,
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USA). Baseline characteristics and echocardiography parameters are expressed as mean values ± one standard error of the mean. Shapiro-Wilk test was used to assess normality of the data. Differences in continuous variables and dichotomous/categorical variables were examined using a Student’s t test or a χ2 square test, respectively. Linear regression analysis was performed to assess
the
relationship
between
continuous
variables
anthropomorphic
data
and
echocardiographic parameters in HFpEF patients with WRF and no WRF. Pearson’s Correlation
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was employed to ascertain the relationship between heart failure outcomes, echocardiographic and demographic. Statistical significance was defined as a two-tailed p-value ≤ 0.05.
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RESULTS
All data is presented as mean ± standard deviation. Of 434 patients hospitalized for heart failure during the study period, 206 patients (47%) met the predefined criteria for HFpEF. The
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final study population consisted of 104 HFpEF patients with technically adequate echocardiograms during their hospitalization to allow for comprehensive right-sided cardiac
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analysis by echocardiogram. The majority of our 104 patients were women (62%), Black (70%) with a mean age of 62 ± 13 years and New York Heart Association (NYHA)8 Class II symptoms of heart failure on admission. The majority of patients were hypertensive (84%), with high rates of metabolic syndrome (62%) and diabetes mellitus (57%). Additional demographic and clinical
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characteristics of participants are presented in Table 1.
During the index hospitalization for volume overload in this HFpEF cohort, admission blood pressure was 148 ± 34 / 75 ± 17 mmHg with mean admission creatinine (Cr) of 1.6 ± 1.2
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mg/dl. WRF, defined as an increase in serum Cr by ≥ 0.3 mg/dl within the first 72 hours of hospitalization, occurred in 38 of the 104 patients (37%). Age, gender, race, and co-morbid
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conditions were not predictors of WRF, similar to prior observations.6 β-naturetic peptide was not routinely available for analysis. Average length of hospital stay was 8 ± 12 days. There was a mean net fluid loss of 6 ± 9 liters throughout their hospital stay, with net weight loss of 5 ± 10 pounds. Eleven of the 104 patients (11%) were rehospitalized within 30 days of discharge for recurrent heart failure, and 8 (8%) were hospitalized for non-heart failure admissions. There was a 14% 1-year mortality rate overall.
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All 104 HFpEF patients had normal left ventricular systolic function by inclusion criteria, with normal LV cavity size and mild to moderate left ventricular hypertrophy as shown in Table 2. Mitral inflow pattern ratio of early (E) and late (A) diastolic velocities were suggestive of
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Grade 1 diastolic dysfunction, with elevated LV filling pressures (septal E/e’=15.4 ± 7.4). Mean tissue Doppler derived medial e’velocity was reduced at 7.3 ± 2.7 cm/s. RA area (RAA) was elevated, as was linear dimension of the RV base. Mean RV fractional area change was 44.7 ±
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0.1 % and RVSP was elevated (49.4 ± 18 mmHg). The prevalence of abnormal RV FAC, defined by ASE cuttoff of <35%,15 was 9% in our HFpEF cohort. Fifty-five of the 104 patients (53%)
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had pulmonary hypertension, defined as RVSP ≥ 35 mmHg, with an average RVSP of 52 ± 14 mmHg in this subgroup.
Echocardiographic parameters of HFpEF patients were analyzed according to WRF status, demonstrated in Table 3. There was no significant difference in mean RV basal diameter
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between groups or RA area. However, RV wall thickness was significantly increased in HFpEF patients with WRF compared to those without WRF (p= 0.001). In terms of RV functional parameters, RV FAC (fractional area change, reflective of RV function) was significantly lower
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in the WRF group compared to the no WRF group, Table 3 With regards to hemodynamic parameters and diastolic assessment, E/A ratio was not
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significantly different between groups (p=0.49). There were no significant differences in either LV medial E/e’ ratio or RVSP (Table 3). Finally, estimated RA pressure (RAP) was higher in the WRF group compared to the no WRF group approaching statistical significance.
DISCUSSION
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In the present study of a diverse, urban cohort of HFpEF patients, detailed echocardiographic analysis of right sided structural and hemodynamic parameters revealed that RV dysfunction, reflected by reduced RV FAC was significantly related to WRF in patients
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admitted for heart failure. WRF during inpatient hospitalization has been shown to portend poor mortality and morbidities outcomes in heart failure, with most studies focusing on heart failure with reduced ejection fraction.12,17 Sharma et al described a higher rate of WRF during
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hospitalization for decompensated HFpEF in an urban HFpEF population than previously reported in other cohorts.6 In the present study, we focused on a subset of HFpEF patients with
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technically adequate 2D echocardiograms allowing comprehensive RV analysis, the majority of which were performed during the index hospitalization for heart failure. Our HFpEF cohort had baseline renal dysfunction as evidenced by elevation in mean admission Cr (Table 1). With regards to WRF status, we observed no significant difference in linear dimensions of RV
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chamber size between groups. However, there was a significantly higher RA pressure and lower in RV FAC in the WRF group compared to no WRF group, primarily due to an increase in RV systolic area (Table 3). To our knowledge, this is the first report in a community based HFpEF
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population demonstrating a significant association between RV dysfunction and worsening renal function in the acute heart failure setting. Our findings are of particular importance given the
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diverse nature of our cohort with a large proportion of Black participants, an underrepresented study population with exceedingly high mortality from HFpEF.9 Prior studies in heart failure patients demonstrated that measures of RV dysfunction have
strong predictive value for mortality and heart failure rehospitalizations.18 In the present study, we utilized RV FAC as a surrogate for RVEF, and observed decreased RV FAC in hospitalized HFpEF patients with WRF compared to those without WRF. RV FAC is a quantitative measure
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of RV function that is accurate, reproducible, standardized in imaging guidelines,15 and used extensively in the heart failure literature.1,3,19 Our study reported an overall prevalence of abnormal RV FAC (defined by ASE cuttoff of <35%) of 9% overall, comparable to prior
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reports.20 To our knowledge, this is the first study to demonstrate reduced RV FAC by WRF status, suggestive of impaired RV function in this group of hospitalized HFpEF patients. RV function and contractile reserve was previously shown to be a predictor of functional capacity
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and mortality in patients with pulmonary hypertension (PH), and more recently in HFpEF.21-23 However, in the present study, we observed RV dysfunction despite no significant group
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differences in LV medial E/e’ ratio and RVSP, suggesting that findings of diminished FAC were not solely due to elevation in filling pressures in decompensated heart failure. These findings may be explained by differences in pulmonary vascular resistance between groups, although this was not specifically assessed in the current study. Taken together, the RV dysfunction observed
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in this study may be mutifactorial and merits further investigation in larger populations. Patients in the WRF group had increased RV free wall thickness compared to the no WRF group, suggestive of some degree of chronicity of RV dysfunction and remodeling,
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possibly due to an adaptative response to chronic or recurrent elevations in pulmonary pressure. PH associated with HFpEF is more common than previously recognized and is associated with
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hypertension in symptomatic elderly women with impaired GFR.24,25 Although we observed a statistically significant difference in RV wall thickness in WRF compared to no WRF HFpEF patients, the relative difference in wall thickness was small (<1 mm).
Therefore, the
measurement of RV thickness will need to be validated in larger cohort studies to determine clincial utility and prognostic value. The combination of higher RV wall thickness, lower RV FAC and similar estimated RVSP between the WRF and non-WRF groups raises the possibility
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that the WRF group represents a subgroup of patients with more chronic exposure to elevated pulmonary pressures and perhaps a more advanced disease state that is progressing to RV failure.
development of WRF and may portend poor clinical outcomes.
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The characterization of RV dysfunction may help identify HFpEF patients at increased risk for
There were several limitations to the present study. First, the ability to perform comprehensive echocardiographic analysis is largely dependent on 2D image quality, particular
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with regards to detailed analysis of the RV, which can be technically challenging. In addition, our study was limited by its retrospective single-centered nature, where data was abstracted from
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medical records and therefore reliant on adequate reporting and documentation. Finally, while important associations can be made between echocardiographic findings and WRF in HFpEF, our findings cannot be extrapolated as cause and effect.
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DISCLOSURES
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The authors have no conflicts of interest or funding to disclose.
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Variable
n=104
Age (years), mean ± SD
62 ± 13
Women
64 (62%)
Race/Ethnicity 73 (70%)
White
30 (29%)
Other
1 (1%)
Body Mass Index (kg/m2)
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Black
39 ± 13
Admission Creatinine (mg/dl) Creatinine at 48 hours Creatinine at 72 hours Creatinine Difference (mg/dl)
1.6 ± 1.2 1.8 ± 1.3 1.8 ± 1.3
0.3 ± 0.4
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Worsening Renal Failure in first 72 hours of 38 (37%) admission 32 (31%)
NYHA Class I
14 (14%)
NYHA Class III
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NYHA Class IV
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Iodinized Contrast During Hospital Admission
NYHA Class II
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TABLE 1: Baseline Clinical Characteristics of Heart Failure With Preserved Ejection Fraction Cohort
47 (45%) 25 (24%) 17 (17%)
Atrial Fibrillation
25 (24%)
Hypertension
87 (84%)
Prior Myocardial Infarction
16 (16%)
Obstructive Sleep Apnea
11 (33%)
Diabetes Mellitus
59 (57%)
Metabolic Syndrome
61 (62%)
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TABLE 2: Baseline Echocardiographic Characteristics of Heart Failure With Preserved Ejection Fraction Cohort n=104
Left Ventricular Ejection Fraction (%)
60 ± 6
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2D Echocardiographic Parameters
Left Ventricular End Diastolic Diameter (cm)
4.6 ± 0.7
Left Ventricular End Systolic Diameter (cm)
3.1 ± 0.7
Interventricular Septum (cm)
1.3 ± 0.3
1.2 ± 0.2
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Posterior Wall (cm)
100 ± 32
Left Atrial Systolic Diameter (cm)
4.1 ± 0.9
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Left Ventricular Mass Indexed to Body Surface Area (g/m2)
Mitral Inflow E/A Septal E/e’ Right Atrial Area
Right Atrial Area index to BSA (ml/m2) Right Ventricular Base
1.33 ± 0.77 15.4 ± 7.4 21 ± 7.1 6.7 ± 5.4 4.1 ± 0.7 18.2 ± 6.2
Right Ventricular Systolic Area (cm2)
10.1 ± 4.1
Fractional Area Change (%)
45 ± 0.1
Right Ventricular Free Wall Thickness (mm)
4.5 ± 0.8
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Right Ventricular Diastolic Area (cm2)
7.7 ± 4.5
Right Ventricular Systolic Pressure (mm Hg)
49 ± 18
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Right Atrial Pressure (mm Hg)
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No WRF
WRF
LV Ejection Fraction (%)
59 ± 6
61 ± 8
0.25
Mitral Inflow E/A
1.37 ± 0.84
1.25 ± 0.63
0.49
LV Septal E/e’
14.3 ± 6.7
17.6 ± 8.2
0.10
Right Atrial Area (cm2)
21 ± 7
21 ± 7
0.71
Right Ventricular Base (cm)
4.1 ± 0.7
4.0 ± 0.5
0.74
Right Atrial Pressure (mmHg)
7 ± 4.6
9±4
0.05
Right Ventricular Systolic Pressure (mmHg)
47.2 ± 16
46.5 ± 15.2
0.87
Right Ventricular Free Wall thickness (mm)
4.3 ± 0.8
4.9 ± 0.8
0.001
Right Ventricular Diastolic Area (cm2)
18.5 ± 6.7
17.6 ± 5.4
0.54
9.9 ± 4.2
10.5 ± 3.9
0.52
40.6 ± 0.1
0.003
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Right Ventricular Systolic Area (cm2)
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Right Ventricular Fractional Area Change (%) 46.9 ± 0.1
p-value
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Echocardiographic Parameters
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TABLE 3: Differences in Echocardiographic Parameters Between Heart Failure With Preserved Ejection Fraction Patients With And Without Renal Failure