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Magnetic Resonance Assessment of Prevalence and Correlates of Right Ventricular Abnormalities in Isolated Left Ventricular Noncompaction
Magnetic Resonance Assessment of Prevalence and Correlates of Right Ventricular Abnormalities in Isolated Left Ventricular Noncompaction Gaetano Nucifora, MDa,*, Giovanni D. Aquaro, MDb, Pier Giorgio Masci, MDb, Alessandro Pingitore, MDc, and Massimo Lombardi, MDb The aim of the present study was to evaluate the prevalence and correlates of right ventricular (RV) noncompaction (RVNC), RV systolic dysfunction, and RV myocardial fibrosis in patients with isolated left ventricular (LV) noncompaction (LVNC). For this purpose, cine and contrast-enhanced cardiac magnetic resonance imaging (MRI) was used. A total of 56 consecutive patients with isolated LVNC were included in the study. The diagnosis of isolated LVNC was based on the presence of standard cardiac MRI and clinical criteria. For each patient, cine and contrast-enhanced cardiac MR images were analyzed to evaluate the prevalence and correlates of RVNC, RV dysfunction, and late gadolinium enhancement (a surrogate of myocardial fibrosis) involving the RV. Mean age of the patient population was 45 – 19 years; 35 patients (63%) were men. RVNC was observed in 5 patients (9%). Impaired RV systolic function was observed in 9 patients (16%). Late gadolinium enhancement was not observed in any RV segment. No association was found between wall motion abnormalities and noncompaction at RV segmental level (4 coefficient 0.041, p [ 0.26). At multivariate analysis, LV ejection fraction was the only variable independently related to RV ejection fraction (b [ 0.62, p <0.001). In conclusion, RV systolic dysfunction is present in a non-negligible proportion of patients with isolated LVNC; LV systolic function is the only variable independently related to RV systolic function. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;113:142e146) Prominent trabeculations and deep intertrabecular recesses within the left ventricular (LV) wall in the absence of other associated congenital or acquired heart disease are the main characteristics of isolated left ventricular noncompaction (LVNC)1,2; these features are believed to be related to an arrest in the normal embryogenesis of the endocardium and myocardium.3,4 The use of cardiac magnetic resonance imaging (MRI) is of potential clinical value in patients with isolated LVNC. Its high spatial resolution allows precise evaluation of the thickness of compacted and noncompacted myocardial layers and provides the opportunity to quantify biventricular function parameters with high accuracy and reproducibility.5e8 Moreover, contrast-enhanced cardiac magnetic resonance with late gadolinium enhancement (LGE) imaging may detect the area of myocardial fibrosis.9,10 Recent cardiac MRI studies have investigated the relation among LV systolic function, the extent of LVNC, and the presence and/ or extent of LV myocardial fibrosis in this group of
a Cardiothoracic Department, University Hospital “Santa Maria della Misericordia,” Udine, Italy; bMagnetic Resonance Imaging Department, Fondazione Consiglio Nazionale delle Ricerche/Regione Toscana “Gabriele Monasterio,” Pisa, Italy; and cInstitute of Clinical Physiology, Consiglio Nazionale delle Ricerche, Pisa, Italy. Manuscript received June 24, 2013; revised manuscript received and accepted August 26, 2013. See page 145 for disclosure information. *Corresponding author: Tel: (þ39) 0432 552441; fax: (þ39) 0432 482353. E-mail address: [email protected] (G. Nucifora).
0002-9149/13/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.08.049
patients.9e11 Scarce data are conversely available about the associated involvement of the right ventricle (RV) and the clinical meaning of RV systolic dysfunction in this group of patients.12,13 Accordingly, the aim of the present study was to evaluate the prevalence and correlates of RV noncompaction (RVNC), RV systolic dysfunction, and RV myocardial fibrosis in patients with isolated LVNC. For this purpose, cine and contrast-enhanced cardiac MRI was used. Methods A total of 56 consecutive patients with isolated LVNC were included in the study. The diagnosis of isolated LVNC was based on the presence of the following cardiac MRI and clinical criteria5,10: (1) visual appearance of 2 distinct myocardial layers (a compacted epicardial layer and a noncompacted endocardial layer); (2) marked trabeculation and deep intertrabecular recesses within the noncompacted layer; (3) noncompacted/compacted end-diastolic myocardial ratio >2.3; and (4) the absence of other associated congenital or acquired heart disease. The cardiac MRI examinations of these patients were analyzed to evaluate the prevalence and independent correlates of RVNC, RV dysfunction, and RV myocardial fibrosis. Because of the lack of MRI criteria for RVNC, this was considered present when the following criterion derived from previous histopathologic studies was satisfied14,15: the presence of recesses within the inflow area of the RV subjacent to the tricuspid valve involving at least 75% of the RV thickness. All cardiac MRI studies were performed using a 1.5 T scanner (Signa Hdx, GE Healthcare, Milwaukee, Wisconsin). www.ajconline.org
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Figure 1. Lack of association between WMAs and noncompaction (NC) at the RV segmental level (4 coefficient 0.041, p ¼ 0.26).
An 8-element cardiac phased-array receiver surface coil with breath holding in expiration and electrocardiographic gating was used for signal reception. Three standard cine long-axis slices and a stack of contiguous cine short-axis slices from the atrioventricular ring to the apex were acquired using a steadystate free-precession pulse sequence with the following parameters: 30 phases, a slice thickness of 8 mm, no gap, 8 views per segment, number of excitation: 1, field of view of 40 cm, 224 224 matrix, 256 256 reconstruction matrix, a repetition time of 3.5 ms, an echo time of 1.5 ms, a flip angle of 45 , and a bandwidth of 125 KHz. The LGE images were acquired in end-systole in the same view as that used for cine images 10 minutes after intravenous injection of 0.2 mmol/kg gadolinium-diethyltriaminepentaacetic acid (Magnevist, Bayer Schering Pharma, Germany). A segmented inversion-recovery gradient-echo pulse sequence was used with the following parameters: a slice thickness of 8 mm, no gap, number of excitation: 1, field of view of 40 mm, 224 192 matrix, 256 256 reconstruction matrix, a repetition time of 4.6 ms, an echo time of 1.3 ms, and a flip angle of 20 . The appropriate inversion time was set to null normal myocardium (range, 250 to 350 ms). RVNC was determined on cine short-axis slices. First, the RV myocardial segments were visually screened for the presence of deep intertrabecular recesses within the inflow area of the RV subjacent to the tricuspid valve. For this purpose, the Isner classification,16 dividing the RV into 12 segments (4 basal, 4 midventricular, and 4 apical), was used. Thereafter, the ratio of noncompacted (if present) to compacted myocardium was measured for each RV myocardial segment; RVNC was defined as a ratio of noncompacted to compacted myocardium of 3 at end-diastole. Using the same 12-segment model,16 the dichotomous absence or presence of wall motion abnormalities (WMAs) was visually assessed for each RV myocardial segment. Using a dedicated software (MASS Analysis; Medis, Leiden, the Netherlands), the following functional parameters were obtained from the cine short-axis images: RV and LV enddiastolic volume indexes (LVEDVi), RV and LV endsystolic volume index, LV mass index, and RV and LV ejection fractions (RVEF and LVEF, respectively). The dichotomous presence or absence of RV dysfunction (i.e., reduced RVEF) was assessed; previously published cardiac
Figure 2. (A) Short-axis view of cine (steady-state free-precession pulse sequence) cardiac MRI showing multiple areas of noncompaction of both LV (black arrows) and RV (dashed black arrows) myocardium. (B) Shortaxis view of cine cardiac MRI of a patient without RV noncompaction. Black arrows indicate multiple areas of noncompaction of the LV; dashed black arrows indicate the smooth RV myocardium.
MRI ranges for normal RVEF were used as reference values.7 The dichotomous presence or absence of LV LGE was qualitatively determined by reviewing all short- and longaxis contrast-enhanced images; regions of elevated signal intensity had to be confirmed in 2 spatial orientations. The quantitative extent of LV LGE was determined as previously described,17 using a dedicated software (MASS 6.1). A region of interest was selected in the background of the image; mean signal intensity and SD of the region of interest were measured. The LV myocardium was delimited by endocardial and epicardial contours manually traced. Enhanced myocardium was defined as myocardium with a signal intensity of 5 SDs more than the mean of the region of interest.17 The extent of LGE was expressed as percentage of the LV mass (percent LV LGE). For RV LGE, the signal intensity of LV LGE was taken as the reference; an RV segment was considered as having LGE when the enhanced myocardium involved 50% of its circumferential length, as
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Table 1 Characteristics of patients with isolated left ventricular noncompaction related to the presence of right ventricular (RV) systolic dysfunction Variable
RV Systolic Dysfunction No (n ¼ 47)
Age (yrs) Men LVEDVi (ml/m2) LV end-systolic volume index (ml/m2) LVEF (%) LV mass index Number of LV noncompacted segments Presence of LV LGE Extent of LGE expressed as % of LV mass RV end-diastolic volume index (ml/m2) RV end-systolic volume index (ml/m2) RVEF (%) RVNC
43 29 94 44
(25e59) (62) (75e121) (30e66)
55 (44e63) 71 (62e86) 4 (3e5)
p
Yes (n ¼ 9) 57 6 122 80
(43e68) (67) (93e134) (54e93)
0.066 1.00 0.076 0.004
32 (30e37) 102 (72e104) 4 (2e5.5)
<0.001 0.026 0.81
21 (45) 0 (0e5)
8 (89) 6 (3e15)
0.026 0.017
76 (62e91)
81 (69e96)
0.40
25 (20e31)
47 (37e52)
<0.001
67 (60e73) 3 (6)
45 (41e51) 2 (22)
<0.001 0.18
Data are expressed as median (interquartile range) or n (%). Table 2 Univariate and multivariate linear regression analyses to determine the independent correlates of RV systolic function Independent Variable
Age (yrs) Men LVEDVi LVEF LV mass index Number of LV noncompacted segments Extent of LGE expressed as % of LV mass RV end-diastolic volume index RVNC
Univariate
Figure 3. Relation between RVEF and LVEF in patients with isolated LVNC. Straight line: regression line. Dashed curves: 95% confidence intervals for the regression line.
volume index, presence of RVNC, and presence of RV LGE. Only variables with a p value 0.1 at univariate analyses were entered as covariates in the multivariate model. Because of the small population size, the multivariate analysis had exploratory nature. A 2-tailed p value <0.05 was considered statistically significant. Statistical analysis was performed using the SPSS software package (SPSS 19.0; SPSS Inc., Chicago, Illinois).
Multivariate
b
p
b
p
0.29 0.19 0.32 0.62 0.28 0.11
0.031 0.17 0.018 <0.001 0.035 0.42
—
—
— 0.62 —
— <0.001 —
0.34
0.011
—
—
0.20 0.17
0.15 0.21
The dependent variable was RVEF. RV LGE was not entered in the model because it was not observed in any patient.
previously suggested.18 Cine and LGE images were evaluated blindly by 2 independent skilled observers. Continuous variables are expressed as median and interquartile range. Categorical data are presented as absolute numbers and percentages. Differences in continuous variables were assessed using the Student t test or the MannWhitney U test, if appropriate. Chi-square or Fisher’s exact test, if appropriate, were used to assess differences in categorical variables. The 4 coefficient was computed to assess the association between the presence of noncompaction and WMA at the RV segmental level. Univariate and multivariate linear regression analyses (using the backward stepwise model selection procedure) were performed to evaluate the relation between RVEF and the following variables: age, gender, LVEDVi, LVEF, LV mass index, number of LV noncompacted segments, percent LV LGE, RV end-diastolic
Results Mean age of the patient population was 45 19 years; 35 patients (63%) were men. RVNC was observed in 5 patients (9%). Overall, 13 RV segments (2%) fulfilled the definition of noncompaction; the median number of RV noncompacted segments per patient having RVNC was 2 (interquartile range 1.5 to 4) and the maximal noncompacted/compacted myocardium ratio was 5.2 (interquartile range 3.3 to 5.4). Overall, 51 RV segments (8%) showed WMAs; WMAs were similarly observed at the RV basal, mid, and apical levels (18 [35%], 19 [37%], and 14 [28%], respectively). Importantly, no association was found between WMAs and noncompaction at the RV segmental level (4 coefficient 0.041, p ¼ 0.26; Figure 1). LGE was not observed in any RV segment. Figure 2 shows cine cardiac MRI of a patient having multiple areas of noncompaction of both LV and RV myocardium and of a patient without RVNC. Impaired RV systolic function (defined accordingly to previously published cardiac MRI ranges for normal RVEF)7 was observed in 9 patients (16%). Table 1 lists the main differences between patients with and without reduced RVEF. Patients with impaired RV systolic function had higher LVEDVi, LV end-systolic volume index, and LV mass index (p ¼ 0.076, 0.004, and 0.026, respectively). In addition, they showed lower LVEF, higher prevalence of LV LGE, and larger percent LV LGE (p <0.001, p ¼ 0.026, and p ¼ 0.017, respectively). Of note, no significant difference was observed between the 2 groups regarding the number of LV noncompacted segments and the presence of RVNC. Table 2 lists the results of the univariate and multivariate linear regression analyses performed to determine the
Cardiomyopathy/Cardiac MRI/RV in Isolated LVNC
independent correlates of RV systolic function. At the univariate analysis, the following variables were significantly related to RVEF: age, LVEDVi, LVEF, LV mass index, and percent LV LGE. At multivariate analysis, only LVEF was independently related to RVEF (b ¼ 0.62, p <0.001). Figure 3 shows the relation between RVEF and LVEF in patients with isolated LVNC. Discussion The results of the present study can be summarized as follows: (1) RVNC is observed in a minority of patients (9%) with isolated LVNC; (2) impaired RV systolic function is present in a non-negligible proportion (16%) of patients; and (3) of note, RVEF is related to neither the presence of RVNC nor the extent of LVNC; conversely, it is independently related to LVEF. Previous echocardiographic studies have described associated RVNC in 15% to 41% of patients with isolated LVNC.19e21 This high variability is likely related to the suboptimal echocardiographic visualization of the RV. The high spatial resolution of MRI may be of potential clinical value, providing a more accurate and reproducible evaluation of the RV. However, the identification of true RVNC may still be troublesome because of the absence of specific criteria for the diagnosis of RV involvement and because various degrees of RV trabeculations are commonly observed even in normal hearts. Some case reports have previously described, using cardiac MRI, morphologic changes of the RV suggestive for RVNC in adult patients without congenital heart disease.22,23 Similarly, Wlodarska et al12 recently observed a 2-layer structure of the RV muscle with excessive hypertrabeculation in 9 patients initially diagnosed as having arrhythmogenic RV cardiomyopathy. However, specific cutoff values to define RVNC have never been reported. In the present study, RVNC was defined using criteria proposed in previous histopathologic studies.14,15 Because of the normally increased trabeculations in the RV, these criteria suggest that RV involvement should be considered if recesses within the inflow area are present involving at least 75% of the RV thickness.14,15 According to these criteria, we identified RVNC in a minority of patients (9%). Of note, no relation was observed between WMAs and noncompaction at the RV segmental level, and there was no evidence of RV wall fibrosis on postcontrast LGE images. Overall, these findings agree with the hypothesis that noncompaction is a simple phenotypic marker.10 Scarce data are available regarding the prevalence and correlates of RV systolic impairment in isolated LVNC. Leung et al13 recently reported on RV systolic function in a small cohort (n ¼ 14) of consecutive patients with LVNC. In their study, RV dysfunction (defined as RVEF <35%) was identified in 1/2 of the patients; of note, patients with RV dysfunction had significantly lower LVEF and larger LV volumes.13 The present study on a larger cohort of patients with isolated LVNC extends these previous observations, providing insights regarding the correlates of RV systolic function in isolated LVNC. Impaired RV systolic function, which was defined in accordance to previously published cardiac MRI ranges for normal RVEF,7 was observed in 16% of patients; patients with impaired RV systolic function
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had larger LV volumes, lower LV systolic function, larger LV mass index, and larger percent LV LGE. Of note, no relation was observed between RV systolic function and the presence of RVNC; the only independent correlate of RVEF was LVEF. These results further indicate that RV dysfunction is not due to noncompaction involving the RV per se; rather it is a marker of a more advanced disease stage, with more severe impairment of LV systolic function. Follow-up data are obviously required to confirm a casual relation between LV and RV systolic impairments. However, previous studies have demonstrated that the most common cause of RV dysfunction in both nonischemic and ischemic cardiomyopathies is LV dysfunction, through the development of RV pressure overload (because of pulmonary arterial hypertension secondary to chronic pulmonary venous hypertension), ventricular interdependence associated with septal dysfunction and limited pericardial flexibility, neurohormonal interactions, and reduced RV coronary perfusion secondary to decreased systolic driving pressure.24e27 This study has some limitations that should be acknowledged. First, a selection bias may have been introduced as study population included patients presented to a tertiary referral center, which may differ from an unselected group of patients. Second, the study population was relatively small; consequently, multivariate analysis was exploratory and its result needs to be confirmed by further studies with larger sample size. Third, speckle-tracking echocardiography, MRI tagging, or feature-tracking MRI, which allow the quantification of regional myocardial function of the RV using deformation parameters, were not performed. Finally, clinical follow-up data were not available; consequently, no information can be provided about the prognostic role of RV dysfunction in these patients. Of note, several previous studies have reported an association between RVEF and poor outcomes in different heart failure populations26,28e30; larger studies with long-term follow-up are required to confirm this association also in patients with isolated LVNC. Disclosures The authors have no conflicts of interest to disclose. 1. Greutmann M, Mah ML, Silversides CK, Klaassen S, Attenhofer Jost CH, Jenni R, Oechslin EN. Predictors of adverse outcome in adolescents and adults with isolated left ventricular noncompaction. Am J Cardiol 2012;109:276e281. 2. Caliskan K, Michels M, Geleijnse ML, van Domburg RT, van der Boon R, Balk AH, Simoons ML. Frequency of asymptomatic disease among family members with noncompaction cardiomyopathy. Am J Cardiol 2012;110:1512e1517. 3. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006;113:1807e1816. 4. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, Dubourg O, Kuhl U, Maisch B, McKenna WJ, Monserrat L, Pankuweit S, Rapezzi C, Seferovic P, Tavazzi L, Keren A. Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008;29:270e276.
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5. Petersen SE, Selvanayagam JB, Wiesmann F, Robson MD, Francis JM, Anderson RH, Watkins H, Neubauer S. Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging. J Am Coll Cardiol 2005;46:101e105. 6. Maceira AM, Prasad SK, Khan M, Pennell DJ. Normalized left ventricular systolic and diastolic function by steady state free precession cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2006;8:417e426. 7. Maceira AM, Prasad SK, Khan M, Pennell DJ. Reference right ventricular systolic and diastolic function normalized to age, gender and body surface area from steady-state free precession cardiovascular magnetic resonance. Eur Heart J 2006;27:2879e2888. 8. Vonk-Noordegraaf A, Souza R. Cardiac magnetic resonance imaging: what can it add to our knowledge of the right ventricle in pulmonary arterial hypertension? Am J Cardiol 2012;110:25Se31S. 9. Dursun M, Agayev A, Nisli K, Ertugrul T, Onur I, Oflaz H, Yekeler E. MR imaging features of ventricular noncompaction: emphasis on distribution and pattern of fibrosis. Eur J Radiol 2010;74:147e151. 10. Nucifora G, Aquaro GD, Pingitore A, Masci PG, Lombardi M. Myocardial fibrosis in isolated left ventricular non-compaction and its relation to disease severity. Eur J Heart Fail 2011;13:170e176. 11. Cheng H, Zhao S, Jiang S, Lu M, Yan C, Ling J, Zhang Y, Liu Q, Ma N, Yin G, Wan J, Yang Y, Li L, Jerecic R, He Z. Comparison of cardiac magnetic resonance imaging features of isolated left ventricular non-compaction in adults versus dilated cardiomyopathy in adults. Clin Radiol 2011;66:853e860. 12. Wlodarska EK, Wozniak O, Konka M, Piotrowska-Kownacka D, Walczak E, Hoffman P. Isolated ventricular noncompaction mimicking arrhythmogenic right ventricular cardiomyopathy—a study of nine patients. Int J Cardiol 2010;145:107e111. 13. Leung SW, Elayi CS, Charnigo RJ Jr, Syed MA. Clinical significance of right ventricular dysfunction in left ventricular non-compaction cardiomyopathy. Int J Cardiovasc Imaging 2012;28:1123e1131. 14. Burke A, Mont E, Kutys R, Virmani R. Left ventricular noncompaction: a pathological study of 14 cases. Hum Pathol 2005;36: 403e411. 15. Val-Bernal JF, Garijo MF, Rodriguez-Villar D, Val D. Non-compaction of the ventricular myocardium: a cardiomyopathy in search of a pathoanatomical definition. Histol Histopathol 2010;25:495e503. 16. Isner JM, Roberts WC. Right ventricular infarction complicating left ventricular infarction secondary to coronary heart disease. Frequency, location, associated findings and significance from analysis of 236 necropsy patients with acute or healed myocardial infarction. Am J Cardiol 1978;42:885e894. 17. Bondarenko O, Beek AM, Hofman MB, Kuhl HP, Twisk JW, van Dockum WG, Visser CA, van Rossum AC. Standardizing the definition of hyperenhancement in the quantitative assessment of infarct size and myocardial viability using delayed contrast-enhanced CMR. J Cardiovasc Magn Reson 2005;7:481e485. 18. Masci PG, Francone M, Desmet W, Ganame J, Todiere G, Donato R, Siciliano V, Carbone I, Mangia M, Strata E, Catalano C, Lombardi M,
19. 20.
21.
22.
23. 24. 25.
26.
27. 28.
29.
30.
Agati L, Janssens S, Bogaert J. Right ventricular ischemic injury in patients with acute ST-segment elevation myocardial infarction: characterization with cardiovascular magnetic resonance. Circulation 2010;122:1405e1412. Ritter M, Oechslin E, Sutsch G, Attenhofer C, Schneider J, Jenni R. Isolated noncompaction of the myocardium in adults. Mayo Clin Proc 1997;72:26e31. Ichida F, Hamamichi Y, Miyawaki T, Ono Y, Kamiya T, Akagi T, Hamada H, Hirose O, Isobe T, Yamada K, Kurotobi S, Mito H, Miyake T, Murakami Y, Nishi T, Shinohara M, Seguchi M, Tashiro S, Tomimatsu H. Clinical features of isolated noncompaction of the ventricular myocardium: long-term clinical course, hemodynamic properties, and genetic background. J Am Coll Cardiol 1999;34: 233e240. Pignatelli RH, McMahon CJ, Dreyer WJ, Denfield SW, Price J, Belmont JW, Craigen WJ, Wu J, El Said H, Bezold LI, Clunie S, Fernbach S, Bowles NE, Towbin JA. Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Circulation 2003;108:2672e2678. Aquaro GD, Di Bella G, Strata E, Pingitore A, Lombardi M. Threeyear follow-up with cardiac magnetic resonance in a patient with biventricular non-compaction cardiomyopathy. Int J Cardiol 2008;129: e74ee76. Chiribiri A, Leuzzi S, Salvetti I, Patane S, Bonamini R, Trevi GP, Gaita F, Cesarani F. Isolated noncompaction of the right ventricular myocardium in the adulthood? Int J Cardiol 2009;134:e17ee19. Brieke A, DeNofrio D. Right ventricular dysfunction in chronic dilated cardiomyopathy and heart failure. Coron Artery Dis 2005;16:5e11. Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular disease, part II: pathophysiology, clinical importance, and management of right ventricular failure. Circulation 2008;117: 1717e1731. Meyer P, Filippatos GS, Ahmed MI, Iskandrian AE, Bittner V, Perry GJ, White M, Aban IB, Mujib M, Dell’Italia LJ, Ahmed A. Effects of right ventricular ejection fraction on outcomes in chronic systolic heart failure. Circulation 2010;121:252e258. Chin KM, Coghlan G. Characterizing the right ventricle: advancing our knowledge. Am J Cardiol 2012;110:3Se8S. de Groote P, Millaire A, Foucher-Hossein C, Nugue O, Marchandise X, Ducloux G, Lablanche JM. Right ventricular ejection fraction is an independent predictor of survival in patients with moderate heart failure. J Am Coll Cardiol 1998;32:948e954. Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R, Arbustini E, Recusani F, Tavazzi L. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 2001;37:183e188. Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol 2007;49: 2028e2034.
a Cardiothoracic Department, University Hospital “Santa Maria della Misericordia,” Udine, Italy; bMagnetic Resonance Imaging Department, Fondazione Consiglio Nazionale delle Ricerche/Regione Toscana “Gabriele Monasterio,” Pisa, Italy; and cInstitute of Clinical Physiology, Consiglio Nazionale delle Ricerche, Pisa, Italy. Manuscript received June 24, 2013; revised manuscript received and accepted August 26, 2013. See page 145 for disclosure information. *Corresponding author: Tel: (þ39) 0432 552441; fax: (þ39) 0432 482353. E-mail address: [email protected] (G. Nucifora).
0002-9149/13/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.08.049
patients.9e11 Scarce data are conversely available about the associated involvement of the right ventricle (RV) and the clinical meaning of RV systolic dysfunction in this group of patients.12,13 Accordingly, the aim of the present study was to evaluate the prevalence and correlates of RV noncompaction (RVNC), RV systolic dysfunction, and RV myocardial fibrosis in patients with isolated LVNC. For this purpose, cine and contrast-enhanced cardiac MRI was used. Methods A total of 56 consecutive patients with isolated LVNC were included in the study. The diagnosis of isolated LVNC was based on the presence of the following cardiac MRI and clinical criteria5,10: (1) visual appearance of 2 distinct myocardial layers (a compacted epicardial layer and a noncompacted endocardial layer); (2) marked trabeculation and deep intertrabecular recesses within the noncompacted layer; (3) noncompacted/compacted end-diastolic myocardial ratio >2.3; and (4) the absence of other associated congenital or acquired heart disease. The cardiac MRI examinations of these patients were analyzed to evaluate the prevalence and independent correlates of RVNC, RV dysfunction, and RV myocardial fibrosis. Because of the lack of MRI criteria for RVNC, this was considered present when the following criterion derived from previous histopathologic studies was satisfied14,15: the presence of recesses within the inflow area of the RV subjacent to the tricuspid valve involving at least 75% of the RV thickness. All cardiac MRI studies were performed using a 1.5 T scanner (Signa Hdx, GE Healthcare, Milwaukee, Wisconsin). www.ajconline.org
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Figure 1. Lack of association between WMAs and noncompaction (NC) at the RV segmental level (4 coefficient 0.041, p ¼ 0.26).
An 8-element cardiac phased-array receiver surface coil with breath holding in expiration and electrocardiographic gating was used for signal reception. Three standard cine long-axis slices and a stack of contiguous cine short-axis slices from the atrioventricular ring to the apex were acquired using a steadystate free-precession pulse sequence with the following parameters: 30 phases, a slice thickness of 8 mm, no gap, 8 views per segment, number of excitation: 1, field of view of 40 cm, 224 224 matrix, 256 256 reconstruction matrix, a repetition time of 3.5 ms, an echo time of 1.5 ms, a flip angle of 45 , and a bandwidth of 125 KHz. The LGE images were acquired in end-systole in the same view as that used for cine images 10 minutes after intravenous injection of 0.2 mmol/kg gadolinium-diethyltriaminepentaacetic acid (Magnevist, Bayer Schering Pharma, Germany). A segmented inversion-recovery gradient-echo pulse sequence was used with the following parameters: a slice thickness of 8 mm, no gap, number of excitation: 1, field of view of 40 mm, 224 192 matrix, 256 256 reconstruction matrix, a repetition time of 4.6 ms, an echo time of 1.3 ms, and a flip angle of 20 . The appropriate inversion time was set to null normal myocardium (range, 250 to 350 ms). RVNC was determined on cine short-axis slices. First, the RV myocardial segments were visually screened for the presence of deep intertrabecular recesses within the inflow area of the RV subjacent to the tricuspid valve. For this purpose, the Isner classification,16 dividing the RV into 12 segments (4 basal, 4 midventricular, and 4 apical), was used. Thereafter, the ratio of noncompacted (if present) to compacted myocardium was measured for each RV myocardial segment; RVNC was defined as a ratio of noncompacted to compacted myocardium of 3 at end-diastole. Using the same 12-segment model,16 the dichotomous absence or presence of wall motion abnormalities (WMAs) was visually assessed for each RV myocardial segment. Using a dedicated software (MASS Analysis; Medis, Leiden, the Netherlands), the following functional parameters were obtained from the cine short-axis images: RV and LV enddiastolic volume indexes (LVEDVi), RV and LV endsystolic volume index, LV mass index, and RV and LV ejection fractions (RVEF and LVEF, respectively). The dichotomous presence or absence of RV dysfunction (i.e., reduced RVEF) was assessed; previously published cardiac
Figure 2. (A) Short-axis view of cine (steady-state free-precession pulse sequence) cardiac MRI showing multiple areas of noncompaction of both LV (black arrows) and RV (dashed black arrows) myocardium. (B) Shortaxis view of cine cardiac MRI of a patient without RV noncompaction. Black arrows indicate multiple areas of noncompaction of the LV; dashed black arrows indicate the smooth RV myocardium.
MRI ranges for normal RVEF were used as reference values.7 The dichotomous presence or absence of LV LGE was qualitatively determined by reviewing all short- and longaxis contrast-enhanced images; regions of elevated signal intensity had to be confirmed in 2 spatial orientations. The quantitative extent of LV LGE was determined as previously described,17 using a dedicated software (MASS 6.1). A region of interest was selected in the background of the image; mean signal intensity and SD of the region of interest were measured. The LV myocardium was delimited by endocardial and epicardial contours manually traced. Enhanced myocardium was defined as myocardium with a signal intensity of 5 SDs more than the mean of the region of interest.17 The extent of LGE was expressed as percentage of the LV mass (percent LV LGE). For RV LGE, the signal intensity of LV LGE was taken as the reference; an RV segment was considered as having LGE when the enhanced myocardium involved 50% of its circumferential length, as
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Table 1 Characteristics of patients with isolated left ventricular noncompaction related to the presence of right ventricular (RV) systolic dysfunction Variable
RV Systolic Dysfunction No (n ¼ 47)
Age (yrs) Men LVEDVi (ml/m2) LV end-systolic volume index (ml/m2) LVEF (%) LV mass index Number of LV noncompacted segments Presence of LV LGE Extent of LGE expressed as % of LV mass RV end-diastolic volume index (ml/m2) RV end-systolic volume index (ml/m2) RVEF (%) RVNC
43 29 94 44
(25e59) (62) (75e121) (30e66)
55 (44e63) 71 (62e86) 4 (3e5)
p
Yes (n ¼ 9) 57 6 122 80
(43e68) (67) (93e134) (54e93)
0.066 1.00 0.076 0.004
32 (30e37) 102 (72e104) 4 (2e5.5)
<0.001 0.026 0.81
21 (45) 0 (0e5)
8 (89) 6 (3e15)
0.026 0.017
76 (62e91)
81 (69e96)
0.40
25 (20e31)
47 (37e52)
<0.001
67 (60e73) 3 (6)
45 (41e51) 2 (22)
<0.001 0.18
Data are expressed as median (interquartile range) or n (%). Table 2 Univariate and multivariate linear regression analyses to determine the independent correlates of RV systolic function Independent Variable
Age (yrs) Men LVEDVi LVEF LV mass index Number of LV noncompacted segments Extent of LGE expressed as % of LV mass RV end-diastolic volume index RVNC
Univariate
Figure 3. Relation between RVEF and LVEF in patients with isolated LVNC. Straight line: regression line. Dashed curves: 95% confidence intervals for the regression line.
volume index, presence of RVNC, and presence of RV LGE. Only variables with a p value 0.1 at univariate analyses were entered as covariates in the multivariate model. Because of the small population size, the multivariate analysis had exploratory nature. A 2-tailed p value <0.05 was considered statistically significant. Statistical analysis was performed using the SPSS software package (SPSS 19.0; SPSS Inc., Chicago, Illinois).
Multivariate
b
p
b
p
0.29 0.19 0.32 0.62 0.28 0.11
0.031 0.17 0.018 <0.001 0.035 0.42
—
—
— 0.62 —
— <0.001 —
0.34
0.011
—
—
0.20 0.17
0.15 0.21
The dependent variable was RVEF. RV LGE was not entered in the model because it was not observed in any patient.
previously suggested.18 Cine and LGE images were evaluated blindly by 2 independent skilled observers. Continuous variables are expressed as median and interquartile range. Categorical data are presented as absolute numbers and percentages. Differences in continuous variables were assessed using the Student t test or the MannWhitney U test, if appropriate. Chi-square or Fisher’s exact test, if appropriate, were used to assess differences in categorical variables. The 4 coefficient was computed to assess the association between the presence of noncompaction and WMA at the RV segmental level. Univariate and multivariate linear regression analyses (using the backward stepwise model selection procedure) were performed to evaluate the relation between RVEF and the following variables: age, gender, LVEDVi, LVEF, LV mass index, number of LV noncompacted segments, percent LV LGE, RV end-diastolic
Results Mean age of the patient population was 45 19 years; 35 patients (63%) were men. RVNC was observed in 5 patients (9%). Overall, 13 RV segments (2%) fulfilled the definition of noncompaction; the median number of RV noncompacted segments per patient having RVNC was 2 (interquartile range 1.5 to 4) and the maximal noncompacted/compacted myocardium ratio was 5.2 (interquartile range 3.3 to 5.4). Overall, 51 RV segments (8%) showed WMAs; WMAs were similarly observed at the RV basal, mid, and apical levels (18 [35%], 19 [37%], and 14 [28%], respectively). Importantly, no association was found between WMAs and noncompaction at the RV segmental level (4 coefficient 0.041, p ¼ 0.26; Figure 1). LGE was not observed in any RV segment. Figure 2 shows cine cardiac MRI of a patient having multiple areas of noncompaction of both LV and RV myocardium and of a patient without RVNC. Impaired RV systolic function (defined accordingly to previously published cardiac MRI ranges for normal RVEF)7 was observed in 9 patients (16%). Table 1 lists the main differences between patients with and without reduced RVEF. Patients with impaired RV systolic function had higher LVEDVi, LV end-systolic volume index, and LV mass index (p ¼ 0.076, 0.004, and 0.026, respectively). In addition, they showed lower LVEF, higher prevalence of LV LGE, and larger percent LV LGE (p <0.001, p ¼ 0.026, and p ¼ 0.017, respectively). Of note, no significant difference was observed between the 2 groups regarding the number of LV noncompacted segments and the presence of RVNC. Table 2 lists the results of the univariate and multivariate linear regression analyses performed to determine the
Cardiomyopathy/Cardiac MRI/RV in Isolated LVNC
independent correlates of RV systolic function. At the univariate analysis, the following variables were significantly related to RVEF: age, LVEDVi, LVEF, LV mass index, and percent LV LGE. At multivariate analysis, only LVEF was independently related to RVEF (b ¼ 0.62, p <0.001). Figure 3 shows the relation between RVEF and LVEF in patients with isolated LVNC. Discussion The results of the present study can be summarized as follows: (1) RVNC is observed in a minority of patients (9%) with isolated LVNC; (2) impaired RV systolic function is present in a non-negligible proportion (16%) of patients; and (3) of note, RVEF is related to neither the presence of RVNC nor the extent of LVNC; conversely, it is independently related to LVEF. Previous echocardiographic studies have described associated RVNC in 15% to 41% of patients with isolated LVNC.19e21 This high variability is likely related to the suboptimal echocardiographic visualization of the RV. The high spatial resolution of MRI may be of potential clinical value, providing a more accurate and reproducible evaluation of the RV. However, the identification of true RVNC may still be troublesome because of the absence of specific criteria for the diagnosis of RV involvement and because various degrees of RV trabeculations are commonly observed even in normal hearts. Some case reports have previously described, using cardiac MRI, morphologic changes of the RV suggestive for RVNC in adult patients without congenital heart disease.22,23 Similarly, Wlodarska et al12 recently observed a 2-layer structure of the RV muscle with excessive hypertrabeculation in 9 patients initially diagnosed as having arrhythmogenic RV cardiomyopathy. However, specific cutoff values to define RVNC have never been reported. In the present study, RVNC was defined using criteria proposed in previous histopathologic studies.14,15 Because of the normally increased trabeculations in the RV, these criteria suggest that RV involvement should be considered if recesses within the inflow area are present involving at least 75% of the RV thickness.14,15 According to these criteria, we identified RVNC in a minority of patients (9%). Of note, no relation was observed between WMAs and noncompaction at the RV segmental level, and there was no evidence of RV wall fibrosis on postcontrast LGE images. Overall, these findings agree with the hypothesis that noncompaction is a simple phenotypic marker.10 Scarce data are available regarding the prevalence and correlates of RV systolic impairment in isolated LVNC. Leung et al13 recently reported on RV systolic function in a small cohort (n ¼ 14) of consecutive patients with LVNC. In their study, RV dysfunction (defined as RVEF <35%) was identified in 1/2 of the patients; of note, patients with RV dysfunction had significantly lower LVEF and larger LV volumes.13 The present study on a larger cohort of patients with isolated LVNC extends these previous observations, providing insights regarding the correlates of RV systolic function in isolated LVNC. Impaired RV systolic function, which was defined in accordance to previously published cardiac MRI ranges for normal RVEF,7 was observed in 16% of patients; patients with impaired RV systolic function
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had larger LV volumes, lower LV systolic function, larger LV mass index, and larger percent LV LGE. Of note, no relation was observed between RV systolic function and the presence of RVNC; the only independent correlate of RVEF was LVEF. These results further indicate that RV dysfunction is not due to noncompaction involving the RV per se; rather it is a marker of a more advanced disease stage, with more severe impairment of LV systolic function. Follow-up data are obviously required to confirm a casual relation between LV and RV systolic impairments. However, previous studies have demonstrated that the most common cause of RV dysfunction in both nonischemic and ischemic cardiomyopathies is LV dysfunction, through the development of RV pressure overload (because of pulmonary arterial hypertension secondary to chronic pulmonary venous hypertension), ventricular interdependence associated with septal dysfunction and limited pericardial flexibility, neurohormonal interactions, and reduced RV coronary perfusion secondary to decreased systolic driving pressure.24e27 This study has some limitations that should be acknowledged. First, a selection bias may have been introduced as study population included patients presented to a tertiary referral center, which may differ from an unselected group of patients. Second, the study population was relatively small; consequently, multivariate analysis was exploratory and its result needs to be confirmed by further studies with larger sample size. Third, speckle-tracking echocardiography, MRI tagging, or feature-tracking MRI, which allow the quantification of regional myocardial function of the RV using deformation parameters, were not performed. Finally, clinical follow-up data were not available; consequently, no information can be provided about the prognostic role of RV dysfunction in these patients. Of note, several previous studies have reported an association between RVEF and poor outcomes in different heart failure populations26,28e30; larger studies with long-term follow-up are required to confirm this association also in patients with isolated LVNC. Disclosures The authors have no conflicts of interest to disclose. 1. Greutmann M, Mah ML, Silversides CK, Klaassen S, Attenhofer Jost CH, Jenni R, Oechslin EN. Predictors of adverse outcome in adolescents and adults with isolated left ventricular noncompaction. Am J Cardiol 2012;109:276e281. 2. Caliskan K, Michels M, Geleijnse ML, van Domburg RT, van der Boon R, Balk AH, Simoons ML. Frequency of asymptomatic disease among family members with noncompaction cardiomyopathy. Am J Cardiol 2012;110:1512e1517. 3. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006;113:1807e1816. 4. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, Dubourg O, Kuhl U, Maisch B, McKenna WJ, Monserrat L, Pankuweit S, Rapezzi C, Seferovic P, Tavazzi L, Keren A. Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008;29:270e276.
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5. Petersen SE, Selvanayagam JB, Wiesmann F, Robson MD, Francis JM, Anderson RH, Watkins H, Neubauer S. Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging. J Am Coll Cardiol 2005;46:101e105. 6. Maceira AM, Prasad SK, Khan M, Pennell DJ. Normalized left ventricular systolic and diastolic function by steady state free precession cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2006;8:417e426. 7. Maceira AM, Prasad SK, Khan M, Pennell DJ. Reference right ventricular systolic and diastolic function normalized to age, gender and body surface area from steady-state free precession cardiovascular magnetic resonance. Eur Heart J 2006;27:2879e2888. 8. Vonk-Noordegraaf A, Souza R. Cardiac magnetic resonance imaging: what can it add to our knowledge of the right ventricle in pulmonary arterial hypertension? Am J Cardiol 2012;110:25Se31S. 9. Dursun M, Agayev A, Nisli K, Ertugrul T, Onur I, Oflaz H, Yekeler E. MR imaging features of ventricular noncompaction: emphasis on distribution and pattern of fibrosis. Eur J Radiol 2010;74:147e151. 10. Nucifora G, Aquaro GD, Pingitore A, Masci PG, Lombardi M. Myocardial fibrosis in isolated left ventricular non-compaction and its relation to disease severity. Eur J Heart Fail 2011;13:170e176. 11. Cheng H, Zhao S, Jiang S, Lu M, Yan C, Ling J, Zhang Y, Liu Q, Ma N, Yin G, Wan J, Yang Y, Li L, Jerecic R, He Z. Comparison of cardiac magnetic resonance imaging features of isolated left ventricular non-compaction in adults versus dilated cardiomyopathy in adults. Clin Radiol 2011;66:853e860. 12. Wlodarska EK, Wozniak O, Konka M, Piotrowska-Kownacka D, Walczak E, Hoffman P. Isolated ventricular noncompaction mimicking arrhythmogenic right ventricular cardiomyopathy—a study of nine patients. Int J Cardiol 2010;145:107e111. 13. Leung SW, Elayi CS, Charnigo RJ Jr, Syed MA. Clinical significance of right ventricular dysfunction in left ventricular non-compaction cardiomyopathy. Int J Cardiovasc Imaging 2012;28:1123e1131. 14. Burke A, Mont E, Kutys R, Virmani R. Left ventricular noncompaction: a pathological study of 14 cases. Hum Pathol 2005;36: 403e411. 15. Val-Bernal JF, Garijo MF, Rodriguez-Villar D, Val D. Non-compaction of the ventricular myocardium: a cardiomyopathy in search of a pathoanatomical definition. Histol Histopathol 2010;25:495e503. 16. Isner JM, Roberts WC. Right ventricular infarction complicating left ventricular infarction secondary to coronary heart disease. Frequency, location, associated findings and significance from analysis of 236 necropsy patients with acute or healed myocardial infarction. Am J Cardiol 1978;42:885e894. 17. Bondarenko O, Beek AM, Hofman MB, Kuhl HP, Twisk JW, van Dockum WG, Visser CA, van Rossum AC. Standardizing the definition of hyperenhancement in the quantitative assessment of infarct size and myocardial viability using delayed contrast-enhanced CMR. J Cardiovasc Magn Reson 2005;7:481e485. 18. Masci PG, Francone M, Desmet W, Ganame J, Todiere G, Donato R, Siciliano V, Carbone I, Mangia M, Strata E, Catalano C, Lombardi M,
19. 20.
21.
22.
23. 24. 25.
26.
27. 28.
29.
30.
Agati L, Janssens S, Bogaert J. Right ventricular ischemic injury in patients with acute ST-segment elevation myocardial infarction: characterization with cardiovascular magnetic resonance. Circulation 2010;122:1405e1412. Ritter M, Oechslin E, Sutsch G, Attenhofer C, Schneider J, Jenni R. Isolated noncompaction of the myocardium in adults. Mayo Clin Proc 1997;72:26e31. Ichida F, Hamamichi Y, Miyawaki T, Ono Y, Kamiya T, Akagi T, Hamada H, Hirose O, Isobe T, Yamada K, Kurotobi S, Mito H, Miyake T, Murakami Y, Nishi T, Shinohara M, Seguchi M, Tashiro S, Tomimatsu H. Clinical features of isolated noncompaction of the ventricular myocardium: long-term clinical course, hemodynamic properties, and genetic background. J Am Coll Cardiol 1999;34: 233e240. Pignatelli RH, McMahon CJ, Dreyer WJ, Denfield SW, Price J, Belmont JW, Craigen WJ, Wu J, El Said H, Bezold LI, Clunie S, Fernbach S, Bowles NE, Towbin JA. Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Circulation 2003;108:2672e2678. Aquaro GD, Di Bella G, Strata E, Pingitore A, Lombardi M. Threeyear follow-up with cardiac magnetic resonance in a patient with biventricular non-compaction cardiomyopathy. Int J Cardiol 2008;129: e74ee76. Chiribiri A, Leuzzi S, Salvetti I, Patane S, Bonamini R, Trevi GP, Gaita F, Cesarani F. Isolated noncompaction of the right ventricular myocardium in the adulthood? Int J Cardiol 2009;134:e17ee19. Brieke A, DeNofrio D. Right ventricular dysfunction in chronic dilated cardiomyopathy and heart failure. Coron Artery Dis 2005;16:5e11. Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular disease, part II: pathophysiology, clinical importance, and management of right ventricular failure. Circulation 2008;117: 1717e1731. Meyer P, Filippatos GS, Ahmed MI, Iskandrian AE, Bittner V, Perry GJ, White M, Aban IB, Mujib M, Dell’Italia LJ, Ahmed A. Effects of right ventricular ejection fraction on outcomes in chronic systolic heart failure. Circulation 2010;121:252e258. Chin KM, Coghlan G. Characterizing the right ventricle: advancing our knowledge. Am J Cardiol 2012;110:3Se8S. de Groote P, Millaire A, Foucher-Hossein C, Nugue O, Marchandise X, Ducloux G, Lablanche JM. Right ventricular ejection fraction is an independent predictor of survival in patients with moderate heart failure. J Am Coll Cardiol 1998;32:948e954. Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R, Arbustini E, Recusani F, Tavazzi L. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 2001;37:183e188. Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol 2007;49: 2028e2034.