Author + information
- Received September 21, 2015
- Revision received February 2, 2016
- Accepted February 9, 2016
- Published online April 19, 2016.
- Karl-Philipp Rommel, MDa,
- Maximilian von Roeder, MDa,
- Konrad Latuscynski, BSca,
- Christian Oberueck, BSca,
- Stephan Blazek, MDa,
- Karl Fengler, MDa,
- Christian Besler, MDa,
- Marcus Sandri, MDa,
- Christian Lücke, MDb,
- Matthias Gutberlet, MDb,
- Axel Linke, MDa,
- Gerhard Schuler, MDa and
- Philipp Lurz, MD, PhDa,∗ ()
- aDepartment of Internal Medicine/Cardiology, Leipzig University, Heart Center, Leipzig, Germany
- bDepartment of Radiology, Leipzig University, Heart Center, Leipzig, Germany
- ↵∗Reprint requests and correspondence:
Dr. Philipp Lurz, Department of Internal Medicine/Cardiology, Heart Center of the University of Leipzig, Struempellstrasse 39, 04289 Leipzig, Germany.
Background Optimal patient characterization in heart failure with preserved ejection fraction (HFpEF) is essential to tailor successful treatment strategies. Cardiac magnetic resonance (CMR)–derived T1 mapping can noninvasively quantify diffuse myocardial fibrosis as extracellular volume fraction (ECV).
Objectives This study aimed to elucidate the diagnostic performance of T1 mapping in HFpEF by examining the relationship between ECV and invasively measured parameters of diastolic function. It also investigated the potential of ECV to differentiate among pathomechanisms in HFpEF.
Methods We performed T1 mapping in 24 patients with HFpEF and 12 patients without heart failure symptoms. Pressure-volume loops were obtained with a conductance catheter during basal conditions and handgrip exercise. Transient pre-load reduction was used to extrapolate the diastolic stiffness constant.
Results Patients with HFpEF showed higher ECV (p < 0.01), elevated load-independent passive left ventricular (LV) stiffness constant (beta) (p < 0.001), and a longer time constant of active LV relaxation (p = 0.02). ECV correlated highly with beta (r = 0.75; p < 0.001). Within the HFpEF cohort, patients with ECV greater than the median showed a higher beta (p = 0.05), whereas ECV below the median identified patients with prolonged active LV relaxation (p = 0.01) and a marked hypertensive reaction to exercise due to pathologic arterial elastance (p = 0.04). On multiple linear regression analyses, ECV independently predicted intrinsic LV stiffness (β = 0.75; p < 0.01).
Conclusions Diffuse myocardial fibrosis, assessed by CMR-derived T1 mapping, independently predicts invasively measured LV stiffness in HFpEF. Additionally, ECV helps to noninvasively distinguish the role of passive stiffness and hypertensive exercise response with impaired active relaxation. (Left Ventricular Stiffness vs. Fibrosis Quantification by T1 Mapping in Heart Failure With Preserved Ejection Fraction [STIFFMAP]; NCT02459626)
Heart failure with preserved ejection fraction (HFpEF) is an increasingly common condition accounting for almost one-half of heart failure (HF) cases, thus presenting a major challenge in modern cardiology (1). The prognosis of patients with HF symptoms and sustained systolic function is comparable to patients with reduced systolic function (2). Despite extensive research, all efforts to develop successful treatment strategies have led to unsatisfactory results (3–6). The lack of consistent therapeutic success might partly be explained by the heterogeneous cohort of patients investigated in previous studies, who exhibit exercise intolerance elicited by different pathophysiological mechanisms (7–11). Thus, there is a need to optimize patient characterization to enable scientists and clinicians to successfully tailor individual treatments.
Diastolic dysfunction can frequently be diagnosed in HFpEF patients and is associated with an impairment of active left ventricular (LV) relaxation and/or LV compliance, which in turn results in a disproportional rise in LV filling pressures during exercise (7,12).
Diffuse myocardial fibrosis and an increase in extracellular matrix have been suggested as potential mechanisms for increased LV stiffness and diastolic dysfunction (13–15).
Cardiac magnetic resonance (CMR) imaging is a noninvasive tool that allows reliable characterization of myocardial tissue. With the recent advent of T1 mapping techniques, it has become possible to quantify diffuse changes to the extracellular space. Post-contrast T1 times and extracellular volume fraction (ECV) correlate with histological collagen volume fraction in vivo and in vitro (16,17). The diagnostic value of T1 mapping techniques in patients with HFpEF needs to be further determined.
Invasive tracings of pressure-volume (PV) relations represent the gold standard for assessing left ventricular (LV) load-independent mechanical diastolic properties. Moreover, this technique provides the opportunity to instantly assess different aspects of diastolic function and the end-diastolic pressure–volume relation (EDPVR) under altering loading conditions (18,19).
This study examined the relationship between ECV and invasively measured parameters of diastolic function, and also investigated the potential of ECV to differentiate between different pathomechanisms in HFpEF.
This was a prospective study conducted at the Heart Center, Leipzig University, Germany. Patients with clinical and echocardiographic evidence for HFpEF were included, and patients without HF symptoms but indication for invasive coronary angiography served as control subjects. HFpEF patients were identified according to a consensus paper of the European Society of Cardiology (20), using specific inclusion criteria: left ventricular ejection fraction (LVEF) ≥50%; New York Heart Association functional class ≥II; and E/E′ (explanation in next section) 15 or E/E′ 8 to 15 combined with elevated B-type natriuretic peptide. Patients without HF symptoms served as control subjects; specific inclusion criteria were LVEF >50%, E/E′ <8, as well as normal values of N-terminal pro–B-type natriuretic peptide (NT-proBNP). Exclusion criteria included any relevant coronary artery diseases (CADs), any contraindication to CMR imaging (e.g., pacemaker or cardioverter-defibrillator implants), an estimated glomerular filtration rate <30 ml/min/1.73 m2, acute coronary syndrome, more than moderate valvular diseases, or persistent atrial fibrillation. NT-proBNP levels were analyzed centrally with a standard assay (Cobas, Elecsys NT-proBNP II, Roche, Basel, Switzerland). Assay-specific elevations >220 pg/ml were considered relevant.
To ensure comparable levels of intravascular volumes, CMR imaging and cardiac catheterization were preceded by an intravenous infusion of 500 ml saline solution. To reduce significant confounding, oral medication was withheld on the day of diagnostic workup.
The study was approved by the local ethics committee, and all patients gave written informed consent.
Imaging and testing protocols
Echocardiographic studies were performed on a Vivid 9 system (General Electric Healthcare, Chalfont St. Giles, Great Britain). Mitral valve inflow pattern (E and A velocity), septal and lateral mitral valve annular velocities (E′), as well as the duration of the A wave and the duration of the pulmonary venous flow reversal (Ar), were recorded in an apical 4-chamber view. The ratios of E/A, E/E′ septal, E/E′ lateral, an averaged E/E′, and the difference of Ar-A duration were calculated as markers of diastolic function according to American Society of Echocardiography guidelines (21). Data were analyzed from stored images by an experienced operator (M.vR.) who was unaware of other test results. Measurements were made in 3 cardiac cycles; the average was used for statistical analysis.
Cardiopulmonary exercise testing was performed on a bicycle ergometer. Work rate was increased with a ramp protocol. Breath-by-breath respiratory gas exchange measurements were recorded throughout the test and averaged over a peak width of 20 s at the end of exercise to determine maximum values. Patients were encouraged to exercise until exhaustion.
CMR was performed immediately before invasive catheterization. All scans were performed on an Intera 1.5-T scanner (Koninklijke Philips N.V., Amsterdam, the Netherlands).
The CMR protocol consisted of cine-sequences, T1-weighted spin-echo, and 2-dimensional inversion recovery gradient echo sequences for late enhancement assessment after gadobutrol administration.
T1 mapping was performed with a modified Look-Locker inversion recovery sequence with a 3(3)5 scheme before and 15 min after contrast application (22). Mapping was performed over all available short-axis slices. ECV was calculated on the basis of the combination of pre- and post-contrast T1 mapping data according to the approach proposed by Arheden et al. (23) using the formula: ECV = (ΔR1myocardium/ΔR1blood) • (1 − hematocrit), where R1 = 1/T1 time. A detailed description of the CMR protocol is provided in the Online Appendix.
According to the amount of ECV, we further assigned HFpEF patients to a group on the basis of an ECV greater or less than the median. Data were interpreted by 2 experienced readers who were unaware of the subjects’ clinical information and the results of other diagnostic tests (C.L. and M.G.).
Cardiac catheterization protocol
Standard invasive coronary angiography was performed via right femoral artery access to exclude significant CAD; patients were excluded if they had an indication for the treatment of epicardial stenosis. A conductance catheter (CD Leycom, Hengelo, the Netherlands) was then introduced to record simultaneous LV pressure and volumes as previously described (12). For reduction of pre-load, transient occlusion of the inferior vena cava was achieved by inflation of an Amplatzer sizing balloon (St. Jude Medical, St. Paul, Minnesota). The end-systolic elastance (Ees) was determined as the linear slope through the end-systolic pressure–volume relations (ESPVR), and the load-independent LV stiffness constant (beta) was extrapolated from the EDPVR using the formula EDP = C•ebeta•EDV, where EDP is LV end-diastolic pressure, C is a fitting constant, and EDV is LV end-diastolic volume (24).
To increase afterload, patients were asked to perform handgrip exercise for 1 min, and PV data were acquired at baseline and throughout peak exercise.
The time constant of active relaxation, or tau, was calculated after the method of Mirsky (25), which evaluates the time needed for LV pressure to fall to one-half of its value from peak rate of LV pressure fall (dP/dtmin). Arterial elastance (Ea) was calculated as end-systolic pressure/stroke volume, whereas ventricular arterial coupling was assessed by the formula of end-systolic volume/stroke volume. An experienced operator without knowledge of other test results analyzed the conductance catheter data (K.-P.R.). Further details are provided in the Online Appendix.
Normality of data was assessed using Shapiro-Wilk tests. Data for continuous variables are presented as mean ± SD, if normally distributed, or as median and interquartile range (IQR) if nonnormally distributed. Categorical variables are presented as frequencies and percentages. Comparisons between groups were made using chi-square tests for categorical variables. Continuous variables were compared with unpaired Student t tests or the nonparametric Mann-Whitney U test where appropriate.
Univariate and stepwise multivariate linear regression analyses were performed to identify predictors of beta. Correlations were analyzed with the Pearson method (r = Pearson product moment or standardized coefficient of univariate linear regression).
In a first step, comparisons were made between patients with HFpEF and control subjects. In a second step, HFpEF patients were classified and compared according to their extent of ECV (greater or less than the median). PV loops of 14 patients (providing a total of 28 measurements for each parameter) were assessed by a second observer (K.F.). Reproducibility of PV measurements was tested by the use of linear regression and Bland-Altman limits of agreement. The reproducibility coefficient was calculated as 1.96 × the SD of the differences, as proposed by Bland and Altman (26).
A 2-tailed p value <0.05 was considered statistically significant. SPSS version 20.0 (IBM, Armonk, New York) was used for statistical analyses.
During the study period, 45 patients were considered suitable after echocardiographic assessment. Of these, 2 patients were excluded due to incomplete CMR studies, another 5 excluded due to significant CAD, and 2 due to atrial fibrillation during catheterization. Therefore, 12 patients served as control subjects and 24 patients with HFpEF were included for final analyses.
HFpEF patients were older, were more frequently female, had a higher body mass index, were more likely to have hypertension, and had a numerically higher rate of paroxysmal atrial fibrillation (Table 1). An elevation of NT-proBNP was present in two-thirds of HFpEF patients, who all reported exertional dyspnea, predominantly New York Heart Association functional class II. Patients without HF symptoms presented with indication for coronary angiography due to chest pain and had a significant cardiovascular risk profile. A trend toward a more frequent use of antihypertensive and HF medications was noted in HFpEF patients.
Testing and imaging results
Patients with HFpEF had a significantly impaired exercise capacity in comparison with control subjects (97 W [IQR: 76 to 104 W] vs. 152 W [IQR: 114 to 193 W]; p < 0.01) and a reduced maximal oxygen uptake (16 ml/kg•min [IQR: 14 to 21 ml/kg•min] vs. 25 ml/kg•min [IQR: 21 to 38 ml/kg•min]; p < 0.01).
All patients in the final analysis had complete data for CMR and echocardiographic examinations; patients with HFpEF had bigger left atrial volumes, higher E/E′ ratios, and longer Ar-A durations (Table 2).
Late gadolinium enhancement (LGE) was observed in 4 patients: 2 had inferolateral midwall LGE of unknown etiology, and 2 patients with marked hypertrophy showed focal LGE at the posterior right ventricle insertion. Areas of focal LGE were manually excluded from the analysis. T1 maps were created from a median of 5 (IQR: 5 to 6) ventricular short-axis slices. The ECV was significantly higher in patients with HFpEF.
Correlation of measures of diastolic function
Markers of intrinsic systolic performance (contractility as defined by Ees) and arterial elastance (Ea) were comparable between groups. HFpEF patients had higher LV EDPs at baseline and during exercise as well as a more pronounced increase in EDPVR in response to physical exertion (ΔEDPVR) (Table 3). Patients in the HF group showed prolonged active relaxation during exercise as well as a significantly higher beta. Univariate linear regression demonstrated a significant correlation of the LV stiffness constant with pre-contrast T1 time (r = 0.48; ßnonstandardized = 0.00007; p = 0.003), post-contrast T1 time (r = −0.34; ßnonstandardized = −0.00006; p = 0.04), and ECV (r = 0.75; ßnonstandardized = 0.212; p < 0.01) (Figure 1), as well as with E/E′ (r = 0.59; ßnonstandardized = 0.001; p = 0.04) and left atrial volume index (r = 0.48; ßnonstandardized = 0.0003; p < 0.01).
E/E′ correlated with LV end-diastolic pressure at baseline (r = 0.63; ßnonstandardized = 0.87; p < 0.001) and maximal exercise (r = 0.48; ßnonstandardized = 0.37; p < 0.01), EDPVR at baseline (r = 0.56; ßnonstandardized = 75.2; p < 0.01), and maximal exercise (r = 0.52; ßnonstandardized = 40.4; p < 0.01).
On multivariate linear regression analyses including ECV, E/E′, and left atrial volume index as the noninvasive imaging parameters potentially informing on LV stiffness, ECV emerged as the only independent predictor for intrinsic LV stiffness (ßstandardized = 0.75; ßnonstandardized = 0.21; p < 0.01).
ECV groups in HFpEF patients
When patients with HFpEF were grouped according to the median ECV (32.3%), no differences were observed in baseline characteristics, results of exercise testing, or noninvasive imaging parameters, but the group with ECV greater than the median showed higher ECV (35.4 ± 2.2% vs. 30.3 ± 1.4%; p < 0.01). Echocardiographic measures of diastolic function were comparable for ECV below or above the median: E/E′ 15.0 ± 4.3 vs. 14.6 ± 4.1; p = 0.80; E deceleration time 200 ± 62 ms vs. 201 ± 39 ms; p = 0.97; E/A-ratio 1.0 (IQR: 0.8 to 1.5) vs. 1.0 (IQR: 0.8 to 1.6); p = 0.59; and Ar-A duration 38 ms (IQR: 28 to 51 ms) vs. 38 ms (IQR: 20 to 43 ms); p = 0.66, respectively.
Both groups had a pathological increase in EDPVR during exercise compared with control subjects with no between-group difference (Figure 2, Table 4). Although the group with ECV below the median showed a significantly higher beta, a lower-than-median ECV identified patients with a higher Ea, a hypertensive reaction to physical exercise with markedly elevated filling pressures, and prolonged active relaxation (Figures 2 and 3⇓, Table 4).
Reproducibility of pv-loop measurements
Bland-Altman analysis demonstrated acceptable agreement with the following average differences between measurements: ESPVR −0.07 mm Hg/ml (upper limit of agreement [ULA]: 0.35 mm Hg/ml; lower limit of agreement [LLA]: −0.48 mm Hg/ml); EDPVR 0.0 mm Hg/ml (ULA: 0.05 mm Hg/ml; LLA: −0.05 mm Hg/ml); Ees 0.06 mm Hg/ml (ULA: 0.50 mm Hg/ml; LLA: −0.38 mm Hg/ml); Ea 0.13 mm Hg/ml (ULA: 0.78 mm Hg/ml; LLA: −0.53 mm Hg/ml); beta 0.002 (ULA: 0.011; LLA: −0.007); and tau −0.9 ms (ULA: 5.3 ms; LLA: −7.0 ms) (Online Figure 1). The reproducibility coefficients (given as percent of the average value of the measurements) were: 13% for ESPVR; 34% for EDPVR; 14% for Ees; 28% for Ea; 17% for tau; and 30% for beta. There was no significant proportional bias.
This is the first study comprehensively assessing the diagnostic performance of T1 mapping and determination of ECV in patients with HFpEF. The main findings are: 1) the noninvasively obtainable ECV correlates highly with load-independent LV myocardial stiffness; 2) in patients with HFpEF and a near-normal ECV, predominant pathomechanisms other than myocardial stiffness must be assumed, with a predominant impairment of active relaxation; and 3) ECV assessment allowed for classification of HFpEF patients into 2 groups demonstrating different underlying mechanisms for HFpEF and exercise intolerance.
The emerging clinical problem of patients with HF symptoms despite having a preserved LVEF has led to intensive research and diagnostic algorithms to better understand and ultimately treat these patients (20,27). Problems arise from the heterogeneity of the cohort classified as having HFpEF and the need to individualize possible treatment therapies.
Diastolic dysfunction is the hemodynamic consequence of many pathologies involved in HFpEF. Patients share a pathological upward shift of the EDPVR on exertion (28). Two main determinants of this scenario are an increase in intramyocardial stiffness and a prolongation of active myocardial relaxation (7). Whereas the former is thought to be a consequence of an increase in extracellular matrix (accumulation of collagen and abnormalities of the intramyocardial cytoskeleton), the latter is attributed to an impaired active process of muscular inactivation, asynchronous contraction, or pathological loading conditions (13). Both mechanisms have been demonstrated to play a major role in the development of HFpEF and possibly suggest different treatment targets (7).
Doppler echocardiography provides a foundation to noninvasively diagnose diastolic dysfunction. However, abnormalities found on echocardiographic evaluation are not specific to individuals with HFpEF and are highly load dependent; conclusions as to the underlying pathophysiological processes are limited (29).
The invasive recording of PV relations is the only way to directly assess the heart’s diastolic properties. Therefore, the stiffness constant beta is related to a decreased ventricular compliance, consistent with intrinsic myocardial stiffening (12). Tau, or time constant of isovolumetric relaxation, is a measure of the active relaxation process (25).
CMR T1 mapping techniques have emerged as a noninvasive tool to quantify diffuse myocardial fibroses. Indeed, several studies have found a correlation between histologically proven fibrosis and T1 mapping-derived estimated ECV, and its utility to characterize different cardiac conditions has been demonstrated (16,30–32). Compared with standard T1 mapping techniques, ECV is not affected by many external patient-specific factors, permitting more accurate patient-to-patient comparisons (33). In a recent study, Ellims et al. (14) found that post-contrast T1 times and ECV correlated with beta in heart transplant patients. In their patients, post-contrast T1 time independently predicted beta, allowing them to establish a link between fibrosis and myocardial stiffness. However, their study predominantly examined male cardiac transplant patients with hardly any HF symptoms or signs of diastolic dysfunction and only mildly elevated filling pressures. Moreover, hemodynamic effects during exertion were not examined.
Our study comprehensively evaluated the diagnostic performance of T1 mapping in HFpEF patients compared with control subjects. In line with previous studies, we found that HFpEF patients were predominantly female with multiple cardiovascular risk factors and reduced exercise capacities. Hemodynamically, this could be attributed to a pathological rise of the EDPVR through exercise caused by increased myocardial stiffness and prolongation of active relaxation. We also observed an increased ECV but only a trend toward lower post-contrast T1 times in the HFpEF group. In line with Ellims et al. (14), we found a correlation with post-contrast T1 times and beta. However, ECV was the only independent predictor for the myocardial stiffness constant in multivariate analysis. It should also be noted that, apart from extracellular fibrosis, myocardial wall thickness and alterations of the myocytoskeleton can contribute to myocardial stiffness, which may explain some degree of scatter within the correlation between ECV and beta.
The discrepancies between our study and the work by Ellims et al. (14) might further be explained by the differences in patient characteristics, with an overall higher ECV in our patients (31 ± 4% vs. 26 ± 9%) and different CMR mapping techniques. Our study added the observation that ECV might help differentiate between different aspects of exercise intolerance. When HFpEF patients were classified according to the ECV median, a group with near normal ECVs was generated and compared with a group with elevated ECV. Both groups showed a pathological upward shift of the EDPVR under exercise, which combines both increased intrinsic stiffening and impaired active relaxation. In patients with elevated ECV, the dominant pathomechanism was identified as an increase in passive stiffness. In the other group, patients had a significantly elevated Ea (i.e., arterial stiffness), marked hypertensive reaction to exercise, impaired active relaxation, and development of even higher LV pressures (Figure 3, Central Illustration). Active LV relaxation follows a biphasic course during afterload rise. Although small increases in afterload cause a shortening of tau, afterload excess, as observed in these patients, prolongs relaxation time leading to diastolic dysfunction (34). Although statistically significant differences in active relaxation and passive stiffness could be detected between groups, a relevant overlap between these mechanisms has to be assumed. In fact, patients in the group with ECV below the median showed a significantly higher LV stiffness constant than control subjects. Additionally, in patients with ECV greater than the median, the LV relaxation constant was numerically higher than in control subjects.
Importantly, both groups demonstrated similar echocardiographic findings and were only different when considering the CMR T1 mapping results. These data, therefore, suggest a valuable role of T1 mapping in classifying patients with HFpEF in distinct groups that share the same symptoms and degree of exercise intolerance but exhibit different underlying pathophysiology. Because ECV was the only independent predictor for intrinsic ventricular stiffening, this parameter could be of tremendous value in estimating the contribution of intrinsic ventricular stiffness to HFpEF. Consequently, ECV evaluation might also be used to identify patients for whom an alternative mechanism of diastolic dysfunction is most likely, thus enhancing efforts to better tailor individual treatments.
Given the invasiveness of applied conductance catheter methods, our sample was small, which importantly affects interpretation of the study results. Because multiple statistical testing in a small patient population is susceptible to a type I error, certainly possible in this study, interpretation of our results should be considered “hypothesis-generating” only. Presence of different comorbidities led to some heterogeneity of the small HFpEF patient population, hampering generalizability of our findings. Due to the control group’s defined inclusion criteria (indication for invasive catheterization to exclude CAD), this group showed an extensive cardiovascular risk profile and should not be considered healthy subjects.
Importantly, a group of healthy control subjects may have yielded even clearer differences in hemodynamics and CMR parameters.
Exaggerated by the small sample size, HFpEF patients and control patients differed in age and sex distribution; both have a demonstrated effect on ECV. Although significant confounding of the correlation between CMR-derived ECV and load-independent myocardial stiffness appears unlikely, it cannot be excluded. Separation of patients per ECV exhibited 2 significantly different HFpEF phenotypes. However, relevant overlap between groups is to be expected. Furthermore, ECV might not reflect myocardial stiffening caused by other mechanisms such as myoskeletal alterations. These limitations, along with the small sample size, inhibited the general application of an ECV cutoff value for characterization of HFpEF phenotypes. Echocardiographic diastolic stress was not part of the assessment, but it could have carried some additional diagnostic benefits (35) in this clinical scenario that remain to be determined.
Finally, optimal timing to assess T1 post-contrast maps is disputed (36). It remains unclear whether earlier or later assessment (15-min post-contrast in this study) could improve diagnostic performance.
Diffuse myocardial fibrosis as assessed by CMR-derived T1 mapping independently predicts invasively measured LV stiffness in HFpEF. Although a considerable overlap existed between groups, ECV emerged as a noninvasive way of distinguishing different pathomechanisms in HFpEF. Assessment of ECV could provide additional value in large-scale epidemiological, diagnostic, and therapeutic trials in this field, both in helping to establish certain ECV cutoff values and for subgroup analysis of treatment effects depending on baseline ECV.
COMPETENCY IN MEDICAL KNOWLEDGE: Myocardial fibrosis, as assessed by CMR T1-mapping derived measurement of ECV, correlates with myocardial stiffness and may be useful in identifying the mechanism of diastolic dysfunction in patients with HFpEF.
TRANSLATIONAL OUTLOOK: Further research is warranted to establish the utility of CMR T1 mapping as a guide to clinical decision making in the evaluation and management of patients with HF.
The authors thank Martin Petzold for his support in study organization.
For supplemental Methods and figures, please see the online version of this article.
This study was funded by a research grant from the Heart Center, Leipzig. All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- left ventricular stiffness constant
- arterial elastance
- extracellular volume fraction
- end-diastolic pressure volume relation
- end-systolic elastance
- end-systolic pressure-volume relations
- pressure volume
- time-constant of active left ventricular relaxation
- Received September 21, 2015.
- Revision received February 2, 2016.
- Accepted February 9, 2016.
- American College of Cardiology Foundation
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