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Original Research: PULMONARY VASCULAR DISEASE |

Right Ventricular Strain for Prediction of Survival in Patients With Pulmonary Arterial Hypertension FREE TO VIEW

Arun Sachdev, MD; Hector R. Villarraga, MD; Robert P. Frantz, MD; Michael D. McGoon, MD, FCCP; Ju-Feng Hsiao, MD; Joseph F. Maalouf, MD; Naser M. Ammash, MD; Robert B. McCully, MD; Fletcher A. Miller, MD; Patricia A. Pellikka, MD; Jae K. Oh, MD; Garvan C. Kane, MD, PhD, FCCP
Author and Funding Information

From the Echocardiography Laboratory (Drs Sachdev, Villarraga, Hsiao, Maalouf, Ammash, McCully, Miller, Pellikka, Oh, and Kane); the Pulmonary Hypertension Clinic (Drs Frantz, McGoon, McCully, and Kane), Department of Medicine, Mayo Clinic, Rochester, MN.

Correspondence to: Garvan C. Kane, MD, PhD, FCCP, Pulmonary Hypertension Clinic, Division of Cardiovascular Diseases, Department of Medicine, Gonda 5, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: kane.garvan@mayo.edu


Funding/Support: This work was supported by the Mayo Clinic CR20 program.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;139(6):1299-1309. doi:10.1378/chest.10-2015
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Background:  Pulmonary arterial hypertension (PAH) is a devastating illness of pulmonary vascular remodeling, right-sided heart failure, and limited survival. Whether strain-based measures of right ventricular (RV) systolic function predict future right-sided heart failure and/or death is untested.

Methods:  RV longitudinal systolic strain and strain rate were evaluated by echocardiography in 80 patients with World Health Organization group 1 pulmonary hypertension (PH) (72% were functional class [FC] III or IV). Survival status was assessed over 4 years.

Results:  All patients had a depressed RV systolic strain (−15% ± 5%) and strain rate (−0.80 ± 0.29 s−1). Of the parameters assessed, average RV free wall systolic strain worse than −12.5% identified a cohort with greater severity of disease (82% were FC III/IV), greater RV systolic dysfunction (RV stroke volume index 26 ± 9 mL/m2), and higher right atrial pressure (12 ± 5 mm Hg). Patients with an RV free wall strain worse than −12.5% were associated with a greater degree of disease progression within 6 months, a greater requirement for loop diuretics, and/or a greater degree of lower extremity edema, and it also predicted 1-, 2-, 3-, and 4-year mortality (unadjusted 1-year hazard ratio, 6.2; 2.1–22.3). After adjusting for age, sex, PH cause, and FC, patients had a 2.9-fold higher rate of death per 5% absolute decline in RV free wall strain at 1 year.

Conclusions:  Noninvasive assessment of RV longitudinal systolic strain and strain rate independently predicts future right-sided heart failure, clinical deterioration, and mortality in patients with PAH.

Figures in this Article

Mortality in patients with pulmonary arterial hypertension (PAH) is associated with both severity of symptoms and extent of right-sided heart failure,13 and measures of right ventricular (RV) dysfunction and right atrial (RA) hypertension reflect functional status and are strong predictors of survival.414 However, RV assessment can be challenging. Right-sided heart catheterization (RHC) is invasive, making frequent serial assessment impractical, and the scope of information is limited to pressure/flow-derived variables. RV geometry is complex and, unlike the left ventricle (LV), the predominant orientation of muscle fibers in the RV is in the longitudinal plane. Measures of transverse/radial function do not directly reflect the major component of RV systolic function.1517 Conventional echocardiographic measures of RV longitudinal function, such as tricuspid annular displacement, although of prognostic importance in PAH,18 are by their nature of acquisition prone to error through translational motion and may not adequately reflect RV systolic dysfunction.19 Speckle-tracking strain echocardiography is an easily obtained, angle-independent technique for quantifying myocardial deformation,17,2027 including assessment of RV function in pulmonary hypertension (PH).2831 However, whether RV strain predicts subsequent right-sided heart failure or mortality in patients with PAH is unknown.

Study Population

We studied consecutive adult patients ≥ 18 years of age with PAH, first seen at the Mayo Clinic Rochester, between December 2003 and March 2006, who were naive to PAH-specific therapy. Individuals were included if they fulfilled the contemporary diagnostic criteria for PAH (ie, group 1 PH with mean pulmonary artery pressure [mPAP] ≥ 25 mm Hg at rest occurring in the setting of increases in precapillary pulmonary resistance). Patients with congenital systemic-to-pulmonary shunts were excluded. Two patients were excluded because of hemodynamically significant pericardial effusions and 12 because echocardiographic images were inadequate for the assessment of RV strain by the speckle-tracking method. The remaining 80 patients agreed to the use of their data for research, and the study was approved by the institutional review board (Committee Expedited Review B-IRB 06-005447 and 09-007824).

The estimated glomerular filtration rate was derived by the Modified Diet in Renal Disease equation.32 Clinical status at 6 months was assessed in 73 of the 74 surviving patients based on a clinical evaluation by a member of the PH clinic staff (71 in person, two by telephone, at 5.9 ± 0.9 months). Evidence of right-sided heart failure at follow-up was defined as the presence of more than trivial edema and/or ascites in the setting of neck vein distension. Survival was censored at 4 years with vital status available over this period through clinical follow-up in all subjects.

Echocardiography

Echocardiographic images were reviewed by a study echocardiologist (A. S., J.-F. H., or G. C. K.) unaware of the clinical, laboratory, and hemodynamic information. Two-dimensional (2-D) and Doppler echocardiography were performed according to standard American Society of Echocardiography guidelines.33 The lateral tricuspid annulus systolic excursion distance was measured from 2-D images. Measures of longitudinal excursion by M-mode, which allows superior frame rates and likely more accurate measurements, were not performed routinely. RA pressure estimation was based on interrogation of the inferior vena cava diameter and distensibility and pulse-wave Doppler interrogation of the hepatic vein flow, and was scored as 5, 10, 15, or 20 mm Hg. The mPAP was calculated as the mean trans-tricuspid valve gradient + estimated right atrial pressure (RAP),34 and the diastolic pressure was derived from the equation diastolic PA pressure = (2 × mPAP) − systolic PA pressure. The RV index of myocardial performance (Tei index) was calculated as described.13 PA capacitance was calculated as the Doppler-derived stroke volume/PA pulse pressure.35 The pulmonary vascular resistance index (PVRI) was calculated as the mean PA pulse pressure divided by the cardiac index.36

RV Strain and Strain Rate

A three-beat, 2-D, digital clip of apical four-chamber view of the RV (average frame rate 39.4 ± 11 frames/s) was transferred to a Syngo Vector Velocity Imaging workstation (Siemens Medical Solutions; Mountain View, California) for analysis of systolic strain, time-to-peak systolic strain, and systolic and diastolic strain rate. The RV endocardium was traced with 10 to 15 points starting and ending at the tricuspid valve annulus. Negative strain values indicate tissue shortening/contraction. Positive strain values indicate tissue lengthening. A global RV value was calculated by averaging the value of six segments. Mean values of the septal and lateral free walls were also calculated. The correlation coefficient in a subgroup (n = 10) blinded assessment of intraobserver variability was 0.91 for RV free wall strain and 0.82 for RV free wall systolic strain rate (blinded repeat review performed 8 weeks after initial review) and for interobserver variability was 0.89 for RV free wall strain and 0.63 for RV free wall systolic strain rate.

Invasive Hemodynamics

Acute vasodilator testing was performed in the majority (n = 65) with a positive vasodilator response defined as a fall in mPAP of ≥ 10 mm Hg to a level of ≤ 40 mm Hg without a concomitant fall in cardiac output.37 The decision as to whether to perform acute vasodilator testing was made by the individual managing PH physician. The reasons not to perform vasodilator testing included active/progressive disease despite calcium channel blocker use or severe World Health Organization (WHO) functional class (FC) IV disease, often in the setting of connective tissue disease.

Data Analysis

Statistical analyses were performed using JMP, version 8.0 (SAS Institute Inc; Cary, North Carolina). Continuous variables were presented as mean ± SD or median with interquartile range and were tested between groups using analysis of variance. Categoric variables were presented as number and percentage, with comparisons by Pearson χ2 analysis.

The distribution of RV free wall strain was separated into thirds, with the lowest tertile being defined as those with an RV free wall strain below −12.5%. The relationship of RV free wall strain to clinical variables and outcomes of interest was assessed either as a continuous or dichotomous variable as outlined. The dichotomous value of above or below −12.5% also corresponded to the optimal cut point on a receiver operating characteristic curve used to test the ability of RV free wall strain to predict 1-year survival. Cox proportional hazards regression models were used to identify correlates of mortality. Results are presented as hazard ratios with 95% CIs. Models were developed with stepwise techniques and with consideration of variables that were clinically relevant. Variables included were RV free wall strain, age, sex, WHO FC, PAH cause, 6-min walk distance, and echocardiographic (RV fractional area change, estimated RAP, Tei index, lateral tricuspid valve annular displacement, and PA capacitance) and RHC (mPAP, mean RAP, cardiac, RV stroke volume, and PVRI) variables. Follow-up of patients is presented based on the Kaplan-Meier product-limit method and compared between groups using the log-rank test. For all analyses, P < .05 was considered to be significant.

The baseline characteristics of the study population are summarized in Table 1 and echocardiographic variables in Table 2. The majority of patients were WHO FC III (63%) or IV (9%), with elevated RAP and PVRI, with significant depression in cardiac index, mixed venous oxygen saturation, and RV stroke volume index. Patients had, on average, moderate-severe/severe enlargement of the RA and RV. Conventional measures of RV function were significantly reduced (lateral tricuspid annular systolic displacement, fractional area change, and RV [Tei] index of myocardial performance).

Table Graphic Jump Location
Table 1 —Characteristics of Study Population

Data are presented as mean ± SD, median (interquartile range), or No. (%), unless otherwise indicated. BNP = brain natriuretic peptide; GFR = glomerular filtration rate; PA = pulmonary artery; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; RA = right atrial; WHO = World Health Organization; WU = Woods unit.

Table Graphic Jump Location
Table 2 —Echocardiographic Characteristics of Study Population

Data are presented as mean ± SD or No. (%). RV = right ventricular. See Table 1 for expansion of other abbreviations.

Twenty patients received parenteral, and seven received inhaled prostacyclin analog therapy; 39 received an oral endothelin receptor antagonist and 28 a phosphodiesterase-5 inhibitor. Seven patients initially received calcium channel blockers alone. Thirty-one were anticoagulated with warfarin to a goal international normalized ratio of 2 to 2.5. Six patients died within 6 months. Of the remaining 73 patients evaluated at 6 months, the average WHO FC was 2.6 ± 0.7 (from 2.8 ± 0.7 at baseline). Forty-three patients reported a similar clinical state, 24 were feeling better, and seven were feeling worse than at baseline. At 6 months, 47 patients were taking diuretic therapy for the management of right-sided heart failure. Of these, 21 had clinical evidence of edema/ascites despite diuretic therapy. The remaining 26 patients had no evidence of right-sided heart failure and were not taking diuretic therapy. Overall survival rates were 82% (95% CI, 71-88) at 1 year and 59% (95% CI, 47-69) at 4 years.

Longitudinal Strain and Strain Rate of RV

Longitudinal RV strain and systolic and early diastolic strain rate were depressed significantly (Figs 1, 2, Table 3). The average RV free wall strain was −15 ± 5% (normal values more negative than −25%).31 Of all the parameters analyzed, an RV free wall strain of worse (less negative) than −12.5% (lowest tertile) was associated with a greater severity of disease, higher levels of B-type natriuretic peptide, higher RA pressure (Fig 3), and marked depression in RV systolic function as measured by echocardiography (Fig 3) or RHC (Fig 4). Furthermore, patients with an RV free wall strain worse than −12.5% were more likely to have smaller LV dimensions (40 ± 5 vs 44 ± 6 mm, P < .01), larger RV dimensions (40 ± 7 vs 37 ± 6 mm, P < .05), greater RV mid-diastolic dimension/LV end-diastolic dimension ratios (1.04 ± 0.3 vs 0.90 ± 0.2, P < .01), moderate to severe or severe tricuspid valve regurgitation (44% vs 28%, P < .05), and a more abnormal RV index of myocardial performance values (Tei index, 0.75 ± 0.26 vs 0.61 ± 0.9; P < .01).

Figure Jump LinkFigure 1. Representative recording from the apical four-chamber view of longitudinal strain, systolic and early diastolic strain rate tracings in a patient with a normal RV. Note each set has seven curves, one for each of the six RV segments and one (in black) for the global RV value. Systolic values are displayed downward (negative) and positive values are above the baseline (positive). The ventricles are displayed in Mayo Clinic format with the LV on the left and the RV on the right. LV = left ventricle; Pk = peak systolic strain; RV = right ventricle; Seg = segment; TPk = time to peak systolic strain.Grahic Jump Location
Figure Jump LinkFigure 2. Representative recording from the apical four-chamber view of RV longitudinal strain, systolic and early diastolic strain rate tracings in a patient with an abnormal RV. Note each set has seven curves, one for each of the six RV segments and one (in black) for the global RV value. Systolic values are displayed downward (negative) and positive values are above the baseline (positive). The ventricles are displayed in Mayo Clinic format with the LV on the left and the RV on the right. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Table Graphic Jump Location
Table 3 —RV Strain and Systolic and Diastolic Strain Rate

Data are presented as mean ± SD. See Table 2 legend for expansion of the abbreviation.

Figure Jump LinkFigure 3. Association of RV free wall systolic strain with clinical and echocardiographic parameters of disease severity and right ventricular dysfunction. A, World Health Organization (WHO) FC. B, BNP. C, RA vol index. D, eRAP by echo. E, RV FAC. F, TV annular systolic displacement. G, RVOT TVI. H, PA CAP. *P < .05. BNP = B-type natriuretic peptide; eRAP = estimated right atrial pressure; FAC = fractional area change; FC = functional class; PA CAP = pulmonary artery capacitance; RA vol = right atrial volume; RVOT = right ventricular outflow tract; TV = tricuspid valve; TVI = time velocity integral. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

Although RV strain data were not available to physicians to influence choice of PAH therapy, those with an RV free wall strain less negative than −12.5%, compared with those with better levels, were less likely to be initially treated with calcium channel blockers alone (0/28 [0%] vs 7/52 [13%], P < .05) and more likely to be treated initially with parenteral prostacyclin analog therapy or an early (within 3 months) combination of an endothelin receptor antagonist, phosphodiesterase-5 inhibitor, and/or an inhaled prostacyclin analog (14/28 [50%] vs 14/52 [27%], P < .05). Despite these differences in early treatment, in those patients alive at 6 months, more abnormal RV free wall strain values were associated with a greater degree of disease progression, with 24% of those with an RV free wall strain > −12.5% having clinical deterioration (Fig 5A). Average WHO FC was also higher at 6 months in those with worse RV free wall strain (3.0 ± 0.7 vs 2.4 ± 0.7, P = .001). Average WHO FC was slightly lower at 6 months in those with a mild to moderate reduction in RV strain (−0.2 ± 0.5, P < .01) but was unchanged in those with severe strain reduction (0.04 ± 0.6, P = .7). Patients with an RV free wall strain worse than −12.5% had a higher requirement of loop diuretics and/or a greater degree of lower extremity edema (Fig 5B) at 6 months, reflecting a greater clinical degree of right-sided heart failure.

Figure Jump LinkFigure 4. Association of RV free wall systolic strain with right-sided heart catheterization findings. A, RAP. B, Mean PAP, mm Hg. C, O2 sat sampled in the main pulmonary artery. D, PVRI for body surface area PVRI). E, RV SV indexed for body surface area. *P < .05. O2 sat = mixed venous oxygen saturation; PAP = pulmonary artery pressure; PVRI = pulmonary vascular resistance index; RAP = right atrial pressure; SV = stroke volume. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 5. Association of tertiles of RV free wall systolic strain. A, With proportion of clinical deterioration at 6-month follow-up (*P < .01). B, With subsequent right-sided heart failure at 6 months as demonstrated by proportion requiring loop diuretics at 6 months and proportion with edema despite diuretics (*P < .01). C, With death over 4 years (P < .005). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

As illustrated in Figure 5C, RV free wall average strain also predicted 1-, 2-, 3-, and 4-year mortality. The 1-, 2-, 3-, and 4-year survival estimates were 61% (95% CI, 42–77), 57% (95% CI, 38–74), 49% (95% CI, 34–67), and 38% (95% CI, 22–57) for those with RV free wall strain less negative than −12.5%; 89% (95% CI, 75–96), 78% (95% CI, 62–89), 67% (95% CI, 51–80), and 66% (95% CI, 49–80) for those with an RV free wall strain between −12.5% and −20%; and 100%, 100%, 93% (95% CI, 65–100) and 83% (95% CI, 50–96) for those with an RV free wall strain < −20%, P < .005. The unadjusted risk of death within the first year with an RV free wall strain > −12.5% was 6.2 (95% CI, 2.1–22.3; P < .001). When assessed as a continuous variable, the unadjusted risk of death within 1 year increased 3.3-fold (95% CI, 1.8–6.8) for every 5% decline in RV free wall strain (Table 4).

Table Graphic Jump Location
Table 4 —Association of RV Strain and Systolic and Diastolic Strain Rate With 2-y Mortality

Data are presented as hazard ratio (lower and upper 95% CIs). HR = hazard ratio; FAC = right ventricular fractional area change by echocardiography, per 5%; FC = functional class; RAP = right atrial pressure measured at right-sided heart catheterization, per 5 mm Hg. See Table 1 for expansion of other abbreviations.

Similar to strain, worsening degrees of RV free wall systolic strain rate were also associated with a greater degree of disease progression at 6 months (Fig 6A), a higher requirement of loop diuretics, and/or a greater degree of lower extremity edema (Fig 5B). RV free wall systolic strain rate also predicted survival with the lowest tertile of RV free wall systolic strain rate (> −0.7 s−1) predicting a particularly poor survival (Fig 6). However, more modest degrees of impairment in systolic strain rate appeared to discriminate less well than RV strain (Fig 6C). The time to peak of the RV peak systolic strain was modestly related to survival, and RV free wall diastolic strain rate was not associated with survival (Table 4).

Figure Jump LinkFigure 6. Association of tertiles of RV free wall systolic strain rate. A, With proportion of clinical deterioration at 6-month follow-up (*P < .01). B, With subsequent right-sided heart failure at 6 months (*P < .01). C, With death over 4 years (P < .005). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

Multivariate models demonstrated that both RV free wall strain and systolic strain rate remained highly predictive of mortality, even when adjusted for age, sex, WHO FC, and PAH cause (Table 4). Although including echocardiographic and catheterization parameters of RV systolic function led to unavoidable colinearity problems in multivariate analysis, RV free wall strain remained predictive of worse outcome regardless of which echocardiographic or catheterization parameter was included in the model (Table 4) and was the strongest predictor of death of all the measures of RV systolic function tested. The concordance index for a model predicting 2-year survival including age, sex, 6-min walk distance, WHO FC, and fractional area change increased from 0.75 to 0.84 with the addition of RV free wall strain.

RV function is an important determinant of outcome in PAH. The assessment of RV function is challenging, however, because of its geometry and the plethora of suggested invasive and noninvasive techniques. Speckle-tracking strain echocardiography has emerged as an easily obtained and angle-independent noninvasive technique for assessing global and regional RV function. Here, the RV longitudinal systolic strain and strain rate were significantly decreased in patients with PAH. An RV free wall strain less negative than −12.5% in patients with PAH identified a cohort of patients with marked RV dysfunction and a marked predisposition to subsequent right-sided heart failure, clinical deterioration, and a high risk of death. The prognostic significance of RV free wall strain persisted after adjusting for basic demographics, FC, cause of PAH, and any alternate parameter of RV systolic function (by echocardiography or RHC).

Although an elevation in PA pressure defines the presence of PH, the degree of RV enlargement, RV contractile dysfunction, and functional parameters that tend to indicate or correlate with impaired contractile dysfunction, such as RA hypertension, pericardial effusion, or severity of tricuspid valve regurgitation, are major determinants of clinical status and mortality.1,3842 To date, a number of echocardiographic and catheter-derived parameters of RV systolic function, some of which appear to have independent prognostic value over clinical data, have been individually linked with outcomes in patients with PAH.13,18,35,39,40,42 Cardiac magnetic resonance-derived measures of RV enlargement have also been associated with outcome.43

The RV has a complex geometry, with muscle fibers that predominantly run in a longitudinal fashion. Unlike in the LV, the majority of contractility in the RV occurs in the longitudinal plane with the base of the RV moving toward the apex in systole.15,16,44 Here, the amount of RV free wall longitudinal deformation (strain) and the rate of this deformation (strain rate) had excellent correlation with conventional clinical, echocardiographic, and catheter-derived measures of RV remodeling. As an angle-independent sensitive measure of global and regional myocardial contractility, strain has the advantage of distinguishing true contractility of the free wall rather than translational motion, a potential concern with singular M-mode or 2-D-derived measures of longitudinal contraction.19,45 Data of strain-based analysis of RV contractility to date have largely focused on the correlation of strain/strain rate with pulmonary artery hemodynamics and/or disease severity and not necessarily in PH cohorts restricted to PAH.2831 To our knowledge, this is the first report on the ability of RV strain/strain rate to correlate not just with clinical, echocardiographic, and catheter-derived measures of RV remodeling and dysfunction, but also with future signs of right-sided heart failure, as well as with survival, in a well-defined cohort with PAH.

We purposely included patients with causes of PAH other than idiopathic and familial PAH. Although they shared similar pathophysiology and it is generally recommended that they be treated in a similar fashion, it is recognized that patients with PAH in the setting of connective tissue disease have a higher mortality.12 Here, RV strain and strain rate predicted outcomes in these PAH patient populations regardless of cause, underscoring the fact that although the rate of death may be different in these groups, the mechanism of progressive RV dysfunction underlying mortality appears to be similarly assessed by this technique. By design, we did not include patients whose PAH was caused by a congenital systemic-to-pulmonary shunt. Therefore, our data may not be extrapolated to this cohort. Because of chronic volume overload, the rate and extent of RV remodeling in this cohort may be different, and whether RV strain and strain rate predicts outcome is less well understood. The tests here were all performed with one software system. Potentially, there may be variations between absolute values measured with different venders’ systems. Doppler-based strain assessment is a potential option for patients in whom images are not satisfactory for speckle-based strain, although it is more dependent on angle and frame rate and is generally felt to be inferior to speckle-based methods. This modality was not tested here. Finally, almost three-quarters of the patients had FC III/IV symptoms at the time of assessment. Although relatively typical for patients diagnosed with PAH,46 our ability to comment on the value of RV strain/strain rate in the assessment of milder/earlier stages of disease is limited. Plausibly, RV myocardial deformation may be a sensitive marker of early RV dysfunction, as has been suggested recently in patients with connective tissue disease47,48 and as is recognized in a number of LV cardiomyopathies.49,50

In conclusion, noninvasive assessment of RV longitudinal systolic function by strain and strain rate independently predicts future right-sided heart failure, clinical deterioration, and mortality in patients with PAH. Speckle-tracking-based strain has the advantage of being widely available, objective, cost effective, and safe. Emerging ultrasound technologies such as speckle-strain may play an important role in predicting prognosis, monitoring the efficacy of specific therapeutic interventions, and detecting preclinical stages of disease in PAH.

Author contributions: Dr Kane had access to the data and takes responsibility for the integrity and accuracy of the data and analysis.

DrSachdev: contributed to study design, data acquisition and analysis, and preparation of the manuscript.

Dr Villarraga: contributed to study design, data analysis, and preparation of the manuscript.

Dr Frantz: contributed to study design, data analysis, and preparation of the manuscript.

Dr McGoon: contributed to study design, data and analysis, and preparation of the manuscript.

Dr Hsiao: contributed to study design, data acquisition and analysis, and preparation of the manuscript.

Dr Maalouf: contributed to study design, data analysis, and preparation of the manuscript.

Dr Ammash: contributed to study design, data analysis, and preparation of the manuscript.

Dr McCully: contributed to study design, data analysis, and preparation of the manuscript.

Dr Miller: contributed to study design, data analysis, and preparation of the manuscript.

Dr Pellikka: contributed to study design, data analysis, and preparation of the manuscript.

Dr Oh: contributed to study design, data analysis, and preparation of the manuscript.

Dr Kane: contributed to study design, data acquisition and analysis, and preparation of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr McGoon has received research funding from Medtronic and Gilead. He has served on advisory, steering and/or end point/data science monitoring board committees for Actelion, Gilead, LungRx, and Medtronic. He has received honoraria for speaking at conferences supported by Actelion and Gilead. Dr Miller is the primary investigator on a research protocol funded by GE Healthcare to assess new echocardiography technology. Drs Sachdev, Villarraga, Frantz, Hsiao, Maalouf, Ammash, McCully, Pellikka, Oh, and Kane have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

2-D

two-dimensional

FC

functional class

LV

left ventricle/ventricular

mPAP

mean pulmonary artery pressure

PAH

pulmonary arterial hypertension

PH

pulmonary hypertension

PVRI

pulmonary vascular resistance index

RA

right atrial

RAP

right atrial pressure

RHC

right-sided heart catheterization

RV

right ventricle

WHO

World Health Organization

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Ingul CB, Torp H, Aase SA, Berg S, Stoylen A, Slordahl SA. Automated analysis of strain rate and strain: feasibility and clinical implications. J Am Soc Echocardiogr. 2005;185:411-418. [CrossRef] [PubMed]
 
Leitman M, Lysyansky P, Sidenko S, et al. Two-dimensional strain-a novel software for real-time quantitative echocardiographic assessment of myocardial function. J Am Soc Echocardiogr. 2004;1710:1021-1029. [CrossRef] [PubMed]
 
Perk G, Tunick PA, Kronzon I. Non-Doppler two-dimensional strain imaging by echocardiography—from technical considerations to clinical applications. J Am Soc Echocardiogr. 2007;203:234-243. [CrossRef] [PubMed]
 
Reisner SA, Lysyansky P, Agmon Y, Mutlak D, Lessick J, Friedman Z. Global longitudinal strain: a novel index of left ventricular systolic function. J Am Soc Echocardiogr. 2004;176:630-633. [CrossRef] [PubMed]
 
Amundsen BH, Helle-Valle T, Edvardsen T, et al. Noninvasive myocardial strain measurement by speckle tracking echocardiography: validation against sonomicrometry and tagged magnetic resonance imaging. J Am Coll Cardiol. 2006;474:789-793. [CrossRef] [PubMed]
 
Hurlburt HM, Aurigemma GP, Hill JC, et al. Direct ultrasound measurement of longitudinal, circumferential, and radial strain using 2-dimensional strain imaging in normal adults. Echocardiography. 2007;247:723-731. [CrossRef] [PubMed]
 
Korinek J, Wang J, Sengupta PP, et al. Two-dimensional strain—a Doppler-independent ultrasound method for quantitation of regional deformation: validation in vitro and in vivo. J Am Soc Echocardiogr. 2005;1812:1247-1253. [CrossRef] [PubMed]
 
Teske AJ, De Boeck BW, Olimulder M, Prakken NH, Doevendans PA, Cramer MJ. Echocardiographic assessment of regional right ventricular function: a head-to-head comparison between 2-dimensional and tissue Doppler-derived strain analysis. J Am Soc Echocardiogr. 2008;213:275-283. [CrossRef] [PubMed]
 
Dambrauskaite V, Delcroix M, Claus P, et al. Regional right ventricular dysfunction in chronic pulmonary hypertension. J Am Soc Echocardiogr. 2007;2010:1172-1180. [CrossRef] [PubMed]
 
Huez S, Vachiéry JL, Unger P, Brimioulle S, Naeije R. Tissue Doppler imaging evaluation of cardiac adaptation to severe pulmonary hypertension. Am J Cardiol. 2007;1009:1473-1478. [CrossRef] [PubMed]
 
Pirat B, McCulloch ML, Zoghbi WA. Evaluation of global and regional right ventricular systolic function in patients with pulmonary hypertension using a novel speckle tracking method. Am J Cardiol. 2006;985:699-704. [CrossRef] [PubMed]
 
Meng H, Villarraga HR, Lee P, et al. Pulmonary hypertension is associated with regional right ventricular systolic dysfunction and dyssynchrony: strain and strain rate assessment using velocity vector imaging technique. Circulation. 2007;116suppl 16:331
 
Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function—measured and estimated glomerular filtration rate. N Engl J Med. 2006;35423:2473-2483. [CrossRef] [PubMed]
 
Lang RM, Bierig M, Devereux RB, et al; Chamber Quantification Writing Group Chamber Quantification Writing Group American Society of Echocardiography’s Guidelines and Standards Committee American Society of Echocardiography’s Guidelines and Standards Committee European Association of Echocardiography European Association of Echocardiography Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;1812:1440-1463. [CrossRef] [PubMed]
 
Aduen JF, Castello R, Lozano MM, et al. An alternative echocardiographic method to estimate mean pulmonary artery pressure: diagnostic and clinical implications. J Am Soc Echocardiogr. 2009;227:814-819. [CrossRef] [PubMed]
 
Mahapatra S, Nishimura RA, Oh JK, McGoon MD. The prognostic value of pulmonary vascular capacitance determined by Doppler echocardiography in patients with pulmonary arterial hypertension. J Am Soc Echocardiogr. 2006;198:1045-1050. [CrossRef] [PubMed]
 
Haddad F, Zamanian R, Beraud AS, et al. A novel non-invasive method of estimating pulmonary vascular resistance in patients with pulmonary arterial hypertension. J Am Soc Echocardiogr. 2009;225:523-529. [CrossRef] [PubMed]
 
Sitbon O, Humbert M, Jaïs X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;11123:3105-3111. [CrossRef] [PubMed]
 
Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984;704:580-587. [CrossRef] [PubMed]
 
Raymond RJ, Hinderliter AL, Willis PW, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002;397:1214-1219. [CrossRef] [PubMed]
 
Champion HC, Michelakis ED, Hassoun PM. Comprehensive invasive and noninvasive approach to the right ventricle-pulmonary circulation unit: state of the art and clinical and research implications. Circulation. 2009;12011:992-1007. [CrossRef] [PubMed]
 
Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;404:780-788. [CrossRef] [PubMed]
 
Ghio S, Klersy C, Magrini G, et al. Prognostic relevance of the echocardiographic assessment of right ventricular function in patients with idiopathic pulmonary arterial hypertension. Int J Cardiol. 2010;1403:272-278. [CrossRef] [PubMed]
 
van Wolferen SA, Marcus JT, Boonstra A, et al. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J. 2007;2810:1250-1257. [CrossRef] [PubMed]
 
Leather HA, Ama’ R, Missant C, Rex S, Rademakers FE, Wouters PF. Longitudinal but not circumferential deformation reflects global contractile function in the right ventricle with open pericardium. Am J Physiol Heart Circ Physiol. 2006;2906:H2369-H2375. [CrossRef] [PubMed]
 
Dandel M, Lehmkuhl HB, Hetzer R, et al. Tricuspid annulus systolic excursion for assessment of right ventricular function: Limitations and sources of misinterpretation in patients with pulmonary hypertension. J Am Soc Echocardiogr. 2010;235:B9. [CrossRef]
 
Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;1372:376-387. [CrossRef] [PubMed]
 
Matias C, Isla LP, Vasconcelos M, et al. Speckle-tracking-derived strain and strain-rate analysis: a technique for the evaluation of early alterations in right ventricle systolic function in patients with systemic sclerosis and normal pulmonary artery pressure. J Cardiovasc Med (Hagerstown). 2009;102:129-134. [CrossRef] [PubMed]
 
Schattke S, Knebel F, Grohmann A, et al. Early right ventricular systolic dysfunction in patients with systemic sclerosis without pulmonary hypertension: a Doppler Tissue and Speckle Tracking echocardiography study. Cardiovasc Ultrasound. 2010;8:3. [CrossRef] [PubMed]
 
Bellavia D, Michelena HI, Martinez M, et al. Speckle myocardial imaging modalities for early detection of myocardial impairment in isolated left ventricular non-compaction. Heart. 2010;966:440-447. [CrossRef] [PubMed]
 
Bellavia D, Pellikka PA, Abraham TP, et al. Evidence of impaired left ventricular systolic function by Doppler myocardial imaging in patients with systemic amyloidosis and no evidence of cardiac involvement by standard two-dimensional and Doppler echocardiography. Am J Cardiol. 2008;1017:1039-1045. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Representative recording from the apical four-chamber view of longitudinal strain, systolic and early diastolic strain rate tracings in a patient with a normal RV. Note each set has seven curves, one for each of the six RV segments and one (in black) for the global RV value. Systolic values are displayed downward (negative) and positive values are above the baseline (positive). The ventricles are displayed in Mayo Clinic format with the LV on the left and the RV on the right. LV = left ventricle; Pk = peak systolic strain; RV = right ventricle; Seg = segment; TPk = time to peak systolic strain.Grahic Jump Location
Figure Jump LinkFigure 2. Representative recording from the apical four-chamber view of RV longitudinal strain, systolic and early diastolic strain rate tracings in a patient with an abnormal RV. Note each set has seven curves, one for each of the six RV segments and one (in black) for the global RV value. Systolic values are displayed downward (negative) and positive values are above the baseline (positive). The ventricles are displayed in Mayo Clinic format with the LV on the left and the RV on the right. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3. Association of RV free wall systolic strain with clinical and echocardiographic parameters of disease severity and right ventricular dysfunction. A, World Health Organization (WHO) FC. B, BNP. C, RA vol index. D, eRAP by echo. E, RV FAC. F, TV annular systolic displacement. G, RVOT TVI. H, PA CAP. *P < .05. BNP = B-type natriuretic peptide; eRAP = estimated right atrial pressure; FAC = fractional area change; FC = functional class; PA CAP = pulmonary artery capacitance; RA vol = right atrial volume; RVOT = right ventricular outflow tract; TV = tricuspid valve; TVI = time velocity integral. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. Association of RV free wall systolic strain with right-sided heart catheterization findings. A, RAP. B, Mean PAP, mm Hg. C, O2 sat sampled in the main pulmonary artery. D, PVRI for body surface area PVRI). E, RV SV indexed for body surface area. *P < .05. O2 sat = mixed venous oxygen saturation; PAP = pulmonary artery pressure; PVRI = pulmonary vascular resistance index; RAP = right atrial pressure; SV = stroke volume. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 5. Association of tertiles of RV free wall systolic strain. A, With proportion of clinical deterioration at 6-month follow-up (*P < .01). B, With subsequent right-sided heart failure at 6 months as demonstrated by proportion requiring loop diuretics at 6 months and proportion with edema despite diuretics (*P < .01). C, With death over 4 years (P < .005). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 6. Association of tertiles of RV free wall systolic strain rate. A, With proportion of clinical deterioration at 6-month follow-up (*P < .01). B, With subsequent right-sided heart failure at 6 months (*P < .01). C, With death over 4 years (P < .005). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Characteristics of Study Population

Data are presented as mean ± SD, median (interquartile range), or No. (%), unless otherwise indicated. BNP = brain natriuretic peptide; GFR = glomerular filtration rate; PA = pulmonary artery; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; RA = right atrial; WHO = World Health Organization; WU = Woods unit.

Table Graphic Jump Location
Table 2 —Echocardiographic Characteristics of Study Population

Data are presented as mean ± SD or No. (%). RV = right ventricular. See Table 1 for expansion of other abbreviations.

Table Graphic Jump Location
Table 3 —RV Strain and Systolic and Diastolic Strain Rate

Data are presented as mean ± SD. See Table 2 legend for expansion of the abbreviation.

Table Graphic Jump Location
Table 4 —Association of RV Strain and Systolic and Diastolic Strain Rate With 2-y Mortality

Data are presented as hazard ratio (lower and upper 95% CIs). HR = hazard ratio; FAC = right ventricular fractional area change by echocardiography, per 5%; FC = functional class; RAP = right atrial pressure measured at right-sided heart catheterization, per 5 mm Hg. See Table 1 for expansion of other abbreviations.

References

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Rushmer RF, Crystal DK, Wagner C. The functional anatomy of ventricular contraction. Circ Res. 1953;12:162-170. [CrossRef] [PubMed]
 
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Langeland S, Wouters PF, Claus P, et al. Experimental assessment of a new research tool for the estimation of two-dimensional myocardial strain. Ultrasound Med Biol. 2006;3210:1509-1513. [CrossRef] [PubMed]
 
Forfia PR, Fisher MR, Mathai SC, et al. Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med. 2006;1749:1034-1041. [CrossRef] [PubMed]
 
Giusca S, Dambrauskaite V, Scheurwegs C, et al. Deformation imaging describes right ventricular function better than longitudinal displacement of the tricuspid ring. Heart. 2010;964:281-288. [CrossRef] [PubMed]
 
Ingul CB, Torp H, Aase SA, Berg S, Stoylen A, Slordahl SA. Automated analysis of strain rate and strain: feasibility and clinical implications. J Am Soc Echocardiogr. 2005;185:411-418. [CrossRef] [PubMed]
 
Leitman M, Lysyansky P, Sidenko S, et al. Two-dimensional strain-a novel software for real-time quantitative echocardiographic assessment of myocardial function. J Am Soc Echocardiogr. 2004;1710:1021-1029. [CrossRef] [PubMed]
 
Perk G, Tunick PA, Kronzon I. Non-Doppler two-dimensional strain imaging by echocardiography—from technical considerations to clinical applications. J Am Soc Echocardiogr. 2007;203:234-243. [CrossRef] [PubMed]
 
Reisner SA, Lysyansky P, Agmon Y, Mutlak D, Lessick J, Friedman Z. Global longitudinal strain: a novel index of left ventricular systolic function. J Am Soc Echocardiogr. 2004;176:630-633. [CrossRef] [PubMed]
 
Amundsen BH, Helle-Valle T, Edvardsen T, et al. Noninvasive myocardial strain measurement by speckle tracking echocardiography: validation against sonomicrometry and tagged magnetic resonance imaging. J Am Coll Cardiol. 2006;474:789-793. [CrossRef] [PubMed]
 
Hurlburt HM, Aurigemma GP, Hill JC, et al. Direct ultrasound measurement of longitudinal, circumferential, and radial strain using 2-dimensional strain imaging in normal adults. Echocardiography. 2007;247:723-731. [CrossRef] [PubMed]
 
Korinek J, Wang J, Sengupta PP, et al. Two-dimensional strain—a Doppler-independent ultrasound method for quantitation of regional deformation: validation in vitro and in vivo. J Am Soc Echocardiogr. 2005;1812:1247-1253. [CrossRef] [PubMed]
 
Teske AJ, De Boeck BW, Olimulder M, Prakken NH, Doevendans PA, Cramer MJ. Echocardiographic assessment of regional right ventricular function: a head-to-head comparison between 2-dimensional and tissue Doppler-derived strain analysis. J Am Soc Echocardiogr. 2008;213:275-283. [CrossRef] [PubMed]
 
Dambrauskaite V, Delcroix M, Claus P, et al. Regional right ventricular dysfunction in chronic pulmonary hypertension. J Am Soc Echocardiogr. 2007;2010:1172-1180. [CrossRef] [PubMed]
 
Huez S, Vachiéry JL, Unger P, Brimioulle S, Naeije R. Tissue Doppler imaging evaluation of cardiac adaptation to severe pulmonary hypertension. Am J Cardiol. 2007;1009:1473-1478. [CrossRef] [PubMed]
 
Pirat B, McCulloch ML, Zoghbi WA. Evaluation of global and regional right ventricular systolic function in patients with pulmonary hypertension using a novel speckle tracking method. Am J Cardiol. 2006;985:699-704. [CrossRef] [PubMed]
 
Meng H, Villarraga HR, Lee P, et al. Pulmonary hypertension is associated with regional right ventricular systolic dysfunction and dyssynchrony: strain and strain rate assessment using velocity vector imaging technique. Circulation. 2007;116suppl 16:331
 
Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function—measured and estimated glomerular filtration rate. N Engl J Med. 2006;35423:2473-2483. [CrossRef] [PubMed]
 
Lang RM, Bierig M, Devereux RB, et al; Chamber Quantification Writing Group Chamber Quantification Writing Group American Society of Echocardiography’s Guidelines and Standards Committee American Society of Echocardiography’s Guidelines and Standards Committee European Association of Echocardiography European Association of Echocardiography Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;1812:1440-1463. [CrossRef] [PubMed]
 
Aduen JF, Castello R, Lozano MM, et al. An alternative echocardiographic method to estimate mean pulmonary artery pressure: diagnostic and clinical implications. J Am Soc Echocardiogr. 2009;227:814-819. [CrossRef] [PubMed]
 
Mahapatra S, Nishimura RA, Oh JK, McGoon MD. The prognostic value of pulmonary vascular capacitance determined by Doppler echocardiography in patients with pulmonary arterial hypertension. J Am Soc Echocardiogr. 2006;198:1045-1050. [CrossRef] [PubMed]
 
Haddad F, Zamanian R, Beraud AS, et al. A novel non-invasive method of estimating pulmonary vascular resistance in patients with pulmonary arterial hypertension. J Am Soc Echocardiogr. 2009;225:523-529. [CrossRef] [PubMed]
 
Sitbon O, Humbert M, Jaïs X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;11123:3105-3111. [CrossRef] [PubMed]
 
Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984;704:580-587. [CrossRef] [PubMed]
 
Raymond RJ, Hinderliter AL, Willis PW, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002;397:1214-1219. [CrossRef] [PubMed]
 
Champion HC, Michelakis ED, Hassoun PM. Comprehensive invasive and noninvasive approach to the right ventricle-pulmonary circulation unit: state of the art and clinical and research implications. Circulation. 2009;12011:992-1007. [CrossRef] [PubMed]
 
Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;404:780-788. [CrossRef] [PubMed]
 
Ghio S, Klersy C, Magrini G, et al. Prognostic relevance of the echocardiographic assessment of right ventricular function in patients with idiopathic pulmonary arterial hypertension. Int J Cardiol. 2010;1403:272-278. [CrossRef] [PubMed]
 
van Wolferen SA, Marcus JT, Boonstra A, et al. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J. 2007;2810:1250-1257. [CrossRef] [PubMed]
 
Leather HA, Ama’ R, Missant C, Rex S, Rademakers FE, Wouters PF. Longitudinal but not circumferential deformation reflects global contractile function in the right ventricle with open pericardium. Am J Physiol Heart Circ Physiol. 2006;2906:H2369-H2375. [CrossRef] [PubMed]
 
Dandel M, Lehmkuhl HB, Hetzer R, et al. Tricuspid annulus systolic excursion for assessment of right ventricular function: Limitations and sources of misinterpretation in patients with pulmonary hypertension. J Am Soc Echocardiogr. 2010;235:B9. [CrossRef]
 
Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;1372:376-387. [CrossRef] [PubMed]
 
Matias C, Isla LP, Vasconcelos M, et al. Speckle-tracking-derived strain and strain-rate analysis: a technique for the evaluation of early alterations in right ventricle systolic function in patients with systemic sclerosis and normal pulmonary artery pressure. J Cardiovasc Med (Hagerstown). 2009;102:129-134. [CrossRef] [PubMed]
 
Schattke S, Knebel F, Grohmann A, et al. Early right ventricular systolic dysfunction in patients with systemic sclerosis without pulmonary hypertension: a Doppler Tissue and Speckle Tracking echocardiography study. Cardiovasc Ultrasound. 2010;8:3. [CrossRef] [PubMed]
 
Bellavia D, Michelena HI, Martinez M, et al. Speckle myocardial imaging modalities for early detection of myocardial impairment in isolated left ventricular non-compaction. Heart. 2010;966:440-447. [CrossRef] [PubMed]
 
Bellavia D, Pellikka PA, Abraham TP, et al. Evidence of impaired left ventricular systolic function by Doppler myocardial imaging in patients with systemic amyloidosis and no evidence of cardiac involvement by standard two-dimensional and Doppler echocardiography. Am J Cardiol. 2008;1017:1039-1045. [CrossRef] [PubMed]
 
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