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Right Ventricular Dyssynchrony in Heart Failure: A Tissue Doppler Imaging Study
Journal of Cardiac Failure Vol. 12 No. 4 2006
Right Ventricular Dyssynchrony in Heart Failure: A Tissue Doppler Imaging Study NAVIN RAJAGOPALAN, MD, KAORU DOHI, MD, MARC A. SIMON, MD, MATTHEW SUFFOLETTO, MD, ´ PEZ-CANDALES, MD KATHY EDELMAN, RDCS, SRINIVAS MURALI, MD, AND ANGEL LO Pittsburgh, Pennsylvania
ABSTRACT Background: The development of right ventricular dysfunction is a poor prognostic sign in patients with heart failure (HF). Although left ventricular dyssynchrony has been well described, it is not known whether right ventricular dyssynchrony coexists in HF. We used tissue Doppler imaging to determine whether right ventricular dyssynchrony is also present in HF patients. Methods and Results: In 34 HF patients (mean age 56 6 13 years), we measured longitudinal strain at the right ventricular free wall, interventricular septum, and left ventricular lateral wall. Right ventricular and left ventricular dyssynchrony were defined as the difference in time to peak strain between the right ventricular free wall and the septum and between the left ventricular lateral wall and septum, respectively. Mean right ventricular dyssynchrony was 59 6 45 ms and the mean left ventricular dyssynchrony was 80 6 62 ms. We found a strong correlation between right ventricular dyssynchrony and pulmonary artery systolic pressure (r 5 0.73; P ! .001) and a negative correlation between right ventricular dyssynchrony and right ventricular fractional area change (r 5 –0.43; P ! .02). Conclusion: HF patients exhibit right ventricular dyssynchrony by strain imaging which correlates with pulmonary hypertension and right ventricular dysfunction. Key Words: Strain, Echocardiography, Pulmonary hypertension.
In patients with advanced heart failure (HF), the presence of right ventricular dysfunction is a powerful predictor of reduced survival.1–3 Assessment of right ventricular function has become essential not only to determine prognosis, but also to guide therapeutic interventions in patients with HF. Unfortunately, current standard methods of evaluating right ventricular function may be limited by the complex shape and poorly defined geometry of the right ventricle that could hinder early identification and progression of right ventricular dysfunction. The recent introduction of strain and strain rate echocardiography using tissue Doppler imaging has provided an
objective means to quantify global and regional left and right ventricular function.4–6 Tissue Doppler imaging has been useful in identifying left ventricular dyssynchrony in patients with HF who may benefit from cardiac resynchronization therapy.7–9 However, little is known regarding right ventricular mechanical activation and whether right ventricular dyssynchrony exists in patients with HF. Recent data have shown that right ventricular dyssynchrony is not only present in patients with pulmonary arterial hypertension and preserved left ventricular function, but that it also significantly correlates with global right ventricular function.10 The aim of this study was to use longitudinal strain imaging in patients with HF to determine if right ventricular dyssynchrony is present in these patients.
From the Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Manuscript received October 3, 2005; revised manuscript received February 5, 2006; revised manuscript accepted February 15, 2006. Reprint requests: Angel Lo´pez-Candales, MD, FACC, FASE, University of Pittsburgh Medical Center, Cardiovascular Institute, Scaife Hall 560, 200 Lothrop Street, Pittsburgh, PA 15213-2582. 1071-9164/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2006.02.008
Methods Patient Population Clinical and echocardiographic data were retrospectively obtained on 34 patients (mean age 56 6 13 years; 30 males) with a clinical history of HF and documented left ventricular ejection fraction #35% who underwent a standard transthoracic echocardiogram with tissue Doppler imaging. All patients had adequate
263
264 Journal of Cardiac Failure Vol. 12 No. 4 May 2006 visualization of the right ventricular free wall and the left ventricular lateral wall in addition to the interventricular septum. Patients with prosthetic valves, a pacer or defibrillator wire in the right ventricle, or a history of cardiac transplantation were all excluded. The study protocol was approved by the University of Pittsburgh Institutional Review Board.
Transthoracic Echocardiography All patients underwent a complete transthoracic echocardiogram including 2-dimensional, color flow, and spectral Doppler as well as tissue Doppler imaging using a GE-Vingmed Vivid 7 system (GE Vingmed Ultrasound, Horten, Norway). Standard 2dimensional echocardiographic evaluation of left and right ventricular size and function was performed. Right ventricular enddiastolic (RVEDA) and end-systolic areas (RVESA) were measured from the apical 4-chamber view to calculate right ventricular fractional area change [RVFAC 5 (RVEDA – RVESA) / RVEDA) 3 100].11 Peak pulmonary artery systolic pressures were estimated by calculating the systolic pressure gradient between the right ventricle and right atrium by the maximum velocity of the tricuspid regurgitant jet using the modified Bernoulli equation, and then adding to this gradient an estimated right atrial pressure based on the size of the inferior vena cava and its variation with respiration.12 Color-coded tissue Doppler cine loops were obtained as routinely performed in our echocardiography laboratory from 3 beats obtained in the apical 4-chamber view at the depths of 14 6 2 cm with pulse repetition frequency set at 1 kHz, Nyquist velocity range 616 cm/second, and frame rates 99 6 9 Hz. Initial length for longitudinal strain assessment was set at 12 mm and regions of interest (20 6 2 mm by 7 6 1 mm) were placed in the basal and mid-ventricular segments of the right ventricular free wall, interventricular septum, and left ventricular lateral wall. For each of the 3 regions, the basal and mid-ventricular measurements were averaged together. Right ventricular mechanical dyssynchrony was defined as the difference in time to peak strain between right ventricular free wall and ventricular septum. Left ventricular lateral wall dyssynchrony was determined as the difference in time to peak strain between the left ventricular lateral wall and the septum. Interventricular dyssynchrony was defined as the difference in time to peak strain between the right ventricular free wall and the left ventricular lateral wall, with a positive value indicating delay of the left ventricular lateral wall compared to the right ventricle.10,13,14
Results Patient Characteristics
Table 1 summarizes major clinical and echocardiographic characteristics. The study population was predominantly male with a mean New York Heart Association class of 2.7 6 0.9. Class 3 and 4 patients consisted the majority of the population (21 patients; 62%), with only 4 patients in New York Heart Association class 1. Mean QRS duration was 124 6 30 ms with 17 patients having QRS duration greater than 120 ms: 10 patients with a complete left bundle branch block morphology and 7 with a right bundle branch block. We were able to obtain a reliable tricuspid regurgitation signal in 30 of the 34 patients to estimate peak pulmonary artery systolic pressure; in the other 4 patients, the tricuspid regurgitation signal was too faint. Endocardial border resolution was adequate in all studies; therefore, we were able to obtain RVFAC in all 34 patients (mean RVFAC 32 6 12%). Strain Analysis
Although the peak longitudinal systolic strain in the interventricular septum was –9.8 6 5.2% and –8.4 6 4.6% in the left ventricular lateral wall, the peak systolic strain was significantly greater in the right ventricular free wall (–18.4 6 4.7%; P ! .001) compared with the other 2 regions. The time to peak longitudinal strain corrected for heart rate in the interventricular septum was 354 6 57 ms and was significantly delayed both in the right ventricular free wall (414 6 49 ms; P ! .001) and in the left ventricular lateral wall (434 6 71 ms; P ! .001). Mean right ventricular dyssynchrony for the entire study population was 59 6 45 ms and mean left ventricular lateral wall dyssynchrony was 80 6 62 ms. Figure 1 shows representative examples of strain imaging of the right ventricular free wall and interventricular septum in 2 patients with HF. Univariate analysis of right ventricular dyssynchrony with clinical and other echocardiographic variables was performed (Table 2). We found a strong correlation between right ventricular dyssynchrony and peak pulmonary artery systolic pressure (r 5 0.73; P ! .001) as shown in Fig. 2. Table 1. Clinical and Echocardiographic Characteristics of 34 HF Patients Characteristics
Statistical Analysis All echocardiographic parameters were calculated using the commercially available software EchoPAC PC version 3.00 (GE Vingmed Ultrasound) and determined by a single observer. All intervals were corrected for heart rate (corrected interval 5 measured interval/[RR interval]1/2).15,16 Group data (mean 6 standard deviation) were compared using the 2-tailed Student’s t-test for paired and unpaired data. Univariate analysis of right ventricular dyssynchrony to various echocardiographic and clinical variables was performed. A P value of !.05 was considered statistically significant.
Mean age Male gender New York Heart Association class Etiology Ischemic Idiopathic QRS duration (ms) LV ejection fraction (%) LV end-diastolic diameter (mm) Peak pulmonary artery systolic pressure (mm Hg) Right ventricular end-diastolic area (cm2) Right ventricular end-systolic area (cm2) Right ventricular fractional area change (%)
Results n 5 34 56 6 13 30 (88%) 2.7 6 0.9 15 (44%) 19 (56%) 124 6 30 22 6 7 63 6 9 46 6 15 26 6 9 19 6 9 32 6 12
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Fig. 2. Strong positive correlation between right ventricular dyssynchrony and peak pulmonary artery systolic pressure in 30 heart failure patients with measurable pulmonary artery pressures.
Fig. 1. A tissue Doppler image demonstrating (A) synchronized time to peak longitudinal strain of the right ventricular free wall (green curve) and the ventricular septum (yellow curve) in a HF patient with normal pulmonary artery pressures and (B) delayed time to peak longitudinal strain of the right ventricular free wall compared to the septum in a heart failure patient with pulmonary hypertension.
A weaker negative correlation between right ventricular dyssynchrony and RVFAC (r 5 –0.43; P ! .02) is shown in Fig. 3. Those patients with moderate or severe right ventricular dysfunction (RVFAC !30%; n 5 15) had significantly greater right ventricular dyssynchrony than the rest of the study population (79 6 44 ms vs. 43 6 41 ms; P ! .02). There was no significant correlation between right ventricular dyssynchrony and QRS duration or between right ventricular dyssynchrony and left ventricular dyssynchrony.
There was no difference in right ventricular dyssynchrony between the ischemic and nonischemic groups, although the groups were not equally represented. Despite having similar peak pulmonary artery systolic pressures (51 6 21 vs. 45 6 14 mm Hg) and RVFAC (30 6 7% vs. 32 6 13%) compared with the rest of the population, patients with right bundle branch block (n 5 7) had greater right ventricular dyssynchrony (86 6 45 ms) than the rest of the population (52 6 44 ms), but this did not reach statistical significance (P 5 .08). Mean interventricular dyssynchrony was 21 6 76 ms with a range from –95 ms to 183 ms. Twelve patients had interventricular dyssynchrony greater than 50 ms, indicating delay of the left ventricular lateral wall compared with the right ventricular free wall; and 7 patients had interventricular dyssynchrony of –50 ms and lower, indicating delay of the right ventricular free wall compared with the left ventricular lateral wall. There was no relationship between interventricular dyssynchrony and RVFAC, peak pulmonary artery systolic pressure, or QRS duration. Discussion This study is the first to depict changes in right ventricular mechanical synchrony in HF patients using strain
Table 2. Univariate Analysis of Right Ventricular Dyssynchrony to Other Clinical and Echocardiographic Variables in HF Patients Variable Age (years) QRS duration (ms) Peak pulmonary artery systolic pressure (mm Hg) Right ventricular end-diastolic area (cm2) Right ventricular end-systolic area (cm2) Right ventricular fractional area change (%) Left ventricular ejection fraction (%) Left ventricular end-diastolic diameter (mm) Right ventricular free wall peak strain (%)
r Value 0.07 0.26 0.73 0.41 0.42 –0.43 0.14 0.34 0.14
P value NS NS !.001 !.02 !.02 !.02 NS NS NS
Fig. 3. Significant negative correlation between right ventricular dyssynchrony and right ventricular fractional area change in all 34 patients.
266 Journal of Cardiac Failure Vol. 12 No. 4 May 2006 imaging echocardiography. We found that in these patients, right ventricular dyssynchrony correlates strongly with peak pulmonary artery systolic pressure and exhibits a negative correlation with global right ventricular function as represented by RVFAC. These findings suggest that, in addition to the presence of left ventricular dyssynchrony, which has been observed in patients with HF, there is also a disturbance of electromechanical coupling within the right ventricle that may contribute to the overall mechanical dyssynchrony seen in patients with HF. We found no correlation between right ventricular dyssynchrony and QRS duration. This is not particularly surprising given that left ventricular dyssynchrony has been reported even with a normal QRS duration.17 HF patients with right bundle branch block have been shown to exhibit left ventricular dyssynchrony,18 but the presence of right ventricular dyssynchrony has not been studied. With right bundle branch block, it would be expected that the magnitude of right ventricular dyssynchrony would be greater given that the free wall of the right ventricle undergoes delayed activation. The result is that much of the right ventricle undergoes activation after activation of the left ventricle has been completed.19,20 We did find that HF patients with right bundle branch block had greater right ventricular dyssynchrony than the rest of the population, despite similar degrees of pulmonary hypertension and global right ventricular function, but the number of patients in this study with right bundle branch block was too small to permit definitive conclusions. Because recent data suggest that about 30% of patients treated with cardiac resynchronization therapy do not show any clinical improvement,21 refinement of the selection process for biventricular pacing is crucial. The presence of right ventricular dyssynchrony may be a possible explanation to account for a significant number of nonresponders to resynchronization therapy. Clinical variables such as ischemic heart disease and a severely dilated left ventricle have been implicated as causes of a lack of response to resynchronization.21,22 However, attention has not been given to measures of right ventricular function. Studies have demonstrated that right ventricular dysfunction is a predictor of worse outcomes in patients with left ventricular dysfunction, so it would not be surprising if abnormalities in right ventricular mechanical activation contribute to the lack of response to resynchronization therapy. It is possible that interventricular dyssynchrony caused by the delay of the right ventricular free wall may not improve with biventricular pacing. Future studies are necessary to determine whether right ventricular dyssynchrony is prevalent in HF patients who are nonresponders to resynchronization. One important question that remains to be answered is whether the presence of right ventricular dyssynchrony should influence the site of right ventricular lead placement in HF patients referred for biventricular pacing. Unfortunately, there are limited sites in the right ventricle to consider for placement of a pacing wire, which can be stable
without the risk of mechanical perforation. In addition, although much research has focused on the left ventricle, little is known regarding right ventricular activation patterns in the presence of pacing in HF patients. Further prospective data analysis is necessary to assess the impact of pacing on improving right ventricular dyssynchrony and function. We recognize that the lack of outcome data and the small number of patients to permit definitive conclusions regarding right bundle branch block are limitations of this study. In addition, we did not obtain invasive pressure measurements; therefore, assessments of right ventricular timepressure plots, dp/dt, and pulmonary vascular resistance were not available. Global right ventricular function was assessed in this study via fractional area change from the 4chamber view. Although RVFAC has been used in previous studies for assessing global right ventricular function,23,24 it is nevertheless dependent on image quality.25 Three patients with atrial fibrillation were included in the study population. Although all time intervals were corrected for heart rate, we acknowledge that the beat-to-beat variations in filling and contraction may affect assessment of dyssynchrony. Finally, it is possible that in some patients the development of pulmonary hypertension and right ventricular dyssynchrony may have been a consequence of pulmonary disease undiagnosed at the time of the echocardiogram as opposed to HF. Our present findings suggest that patients with HF exhibit right ventricular dyssynchrony in addition to left ventricular dyssynchrony. Although right ventricular dyssynchrony was correlated with increasing pulmonary hypertension, a direct cause and effect is beyond the scope of this study, and further studies are needed to determine the sequence of events leading to right ventricular dyssynchrony and the effect of dyssynchrony on clinical outcomes. Furthermore, it is important to determine the effect of cardiac resynchronization therapy on right ventricular dyssynchrony in HF patients.
References 1. Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R, et al. 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;37:183–8. 2. Meluzin J, Spinarova L, Dusek L, Toman J, Hude P, Krejci J. Prognostic importance of the right ventricular function assessed by Doppler tissue imaging. Eur J Echocardiogr 2003;4:262–71. 3. Gavazzi A, Berzuini C, Campana C, Inserra C, Ponzetta M, Sebastiani R, et al. Value of right ventricular ejection fraction in predicting short-term prognosis of patients with severe chronic heart failure. J Heart Lung Transplant 1997;16:774–85. 4. Miyatake K, Yamagishi M, Tanaka N, Uematsu M, Yamazaki N, Mine Y, et al. New method for evaluating left ventricular wall motion by color-coded tissue Doppler imaging: in vitro and in vivo studies. J Am Coll Cardiol 1995;25:717–24. 5. Stoylen A, Heimdal A, Bjornstad K, Torp HG, Skjaerpe T. Strain rate imaging by ultrasound in the diagnosis of regional dysfunction of the left ventricle. Echocardiography 1999;16:321–9.
Right Ventricular Dyssynchrony in Heart Failure 6. Hoffmann R, Altiok E, Nowak B, Heussen N, Kuhl H, Kaiser HJ, et al. Strain rate measurement by doppler echocardiography allows improved assessment of myocardial viability inpatients with depressed left ventricular function. J Am Coll Cardiol 2002;39:443–9. 7. Bax JJ, Ansalone G, Breithardt OA, Derumeaux G, Leclercq C, Schalij MJ, et al. Echocardiographic evaluation of cardiac resynchronization therapy: ready for routine clinical use? A critical appraisal. J Am Coll Cardiol 2004;44:1–9. 8. Bordachar P, Lafitte S, Reuter S, Sanders P, Jais P, Haissaguerre M, et al. Echocardiographic parameters of ventricular dyssynchrony validation in patients with heart failure using sequential biventricular pacing. J Am Coll Cardiol 2004;44:2157–65. 9. Bax JJ, Bleeker GB, Marwick TH, Molhoek SG, Boersma E, Steendijk P, et al. Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol 2004;44:1834–40. 10. Lopez-Candales A, Dohi K, Bazaz R, Edelman K. Relation of right ventricular free wall mechanical delay to right ventricular dysfunction as determined by tissue doppler imaging. Am J Cardiol 2005;96: 602–6. 11. Schenk P, Globits S, Koller J, Brunner C, Artemiou O, Klepetko W, et al. Accuracy of echocardiographic right ventricular parameters in patients with different end-stage lung diseases prior to lung transplantation. J Heart Lung Transplant 2000;19:145–54. 12. Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation 1984;70:657–62. 13. Gorcsan J 3rd, Gulati VK, Mandarino WA, Katz WE. Color-coded measures of myocardial velocity throughout the cardiac cycle by tissue Doppler imaging to quantify regional left ventricular function. Am Heart J 1996;131:1203–13. 14. Gorcsan J 3rd. Tissue Doppler echocardiography. Curr Opin Cardiol 2000;15:323–9. 15. Sade LE, Kanzaki H, Severyn D, Dohi K, Gorcsan J 3rd. Quantification of radial mechanical dyssynchrony in patients with left bundle branch block and idiopathic dilated cardiomyopathy without conduction delay by tissue displacement imaging. Am J Cardiol 2004;94: 514–8.
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16. Ansalone G, Giannantoni P, Ricci R, Trambaiolo P, Fedele F, Santini M. Doppler myocardial imaging to evaluate the effectiveness of pacing sites in patients receiving biventricular pacing. J Am Coll Cardiol 2002;39:489–99. 17. Bleeker GB, Schalij MJ, Molhoek SG, Verwey HF, Holman ER, Boersma E, et al. Relationship between QRS duration and left ventricular dyssynchrony in patients with end-stage heart failure. J Cardiovasc Electrophysiol 2004;15:544–9. 18. Schuster P, Faerestrand S, Ohm OJ. Color Doppler tissue velocity imaging can disclose systolic left ventricular asynchrony independent of the QRS morphology in patients with severe heart failure. Pacing Clin Electrophysiol 2004;27:460–7. 19. Mirvis DM, Goldberger AL. Electrocardiography. In: Braunwald E, Zipes DP, Libby P, editors. Heart disease: a textbook of cardiovascular medicine. Philadelphia: W.B. Saunders Company; 2001. p. 82–128. 20. Fantoni C, Kawabata M, Massaro R, Regoli F, Raffa S, Arora V, et al. Right and left ventricular activation sequence in patients with heart failure and right bundle branch block: a detailed analysis using three-dimensional non-fluoroscopic electroanatomic mapping system. J Cardiovasc Electrophysiol 2005;16:112–9; discussion 120–1. 21. Diaz-Infante E, Mont L, Leal J, Garcia-Bolao I, Fernandez-Lozano I, Hernandez-Madrid A, et al. Predictors of lack of response to resynchronization therapy. Am J Cardiol 2005;95:1436–40. 22. Reuter S, Garrigue S, Barold SS, Jais P, Hocini M, Haissaguerre M, et al. Comparison of characteristics in responders versus nonresponders with biventricular pacing for drug-resistant congestive heart failure. Am J Cardiol 2002;89:346–50. 23. Zornoff LA, Skali H, Pfeffer MA, St John Sutton M, Rouleau JL, Lamas GA, et al. Right ventricular dysfunction and risk of heart failure and mortality after myocardial infarction. J Am Coll Cardiol 2002; 39:1450–5. 24. Katz WE, Gasior TA, Quinlan JJ, Lazar JM, Firestone L, Griffith BP, et al. Immediate effects of lung transplantation on right ventricular morphology and function in patients with variable degrees of pulmonary hypertension. J Am Coll Cardiol 1996;27:384–91. 25. Subramanian U, Weinberger M, Fihn SD, Tierney WM. Diagnostic challenges defining heart failure when using echocardiograms. Am J Cardiol 2003;91:1015–7:A8.
Right Ventricular Dyssynchrony in Heart Failure: A Tissue Doppler Imaging Study NAVIN RAJAGOPALAN, MD, KAORU DOHI, MD, MARC A. SIMON, MD, MATTHEW SUFFOLETTO, MD, ´ PEZ-CANDALES, MD KATHY EDELMAN, RDCS, SRINIVAS MURALI, MD, AND ANGEL LO Pittsburgh, Pennsylvania
ABSTRACT Background: The development of right ventricular dysfunction is a poor prognostic sign in patients with heart failure (HF). Although left ventricular dyssynchrony has been well described, it is not known whether right ventricular dyssynchrony coexists in HF. We used tissue Doppler imaging to determine whether right ventricular dyssynchrony is also present in HF patients. Methods and Results: In 34 HF patients (mean age 56 6 13 years), we measured longitudinal strain at the right ventricular free wall, interventricular septum, and left ventricular lateral wall. Right ventricular and left ventricular dyssynchrony were defined as the difference in time to peak strain between the right ventricular free wall and the septum and between the left ventricular lateral wall and septum, respectively. Mean right ventricular dyssynchrony was 59 6 45 ms and the mean left ventricular dyssynchrony was 80 6 62 ms. We found a strong correlation between right ventricular dyssynchrony and pulmonary artery systolic pressure (r 5 0.73; P ! .001) and a negative correlation between right ventricular dyssynchrony and right ventricular fractional area change (r 5 –0.43; P ! .02). Conclusion: HF patients exhibit right ventricular dyssynchrony by strain imaging which correlates with pulmonary hypertension and right ventricular dysfunction. Key Words: Strain, Echocardiography, Pulmonary hypertension.
In patients with advanced heart failure (HF), the presence of right ventricular dysfunction is a powerful predictor of reduced survival.1–3 Assessment of right ventricular function has become essential not only to determine prognosis, but also to guide therapeutic interventions in patients with HF. Unfortunately, current standard methods of evaluating right ventricular function may be limited by the complex shape and poorly defined geometry of the right ventricle that could hinder early identification and progression of right ventricular dysfunction. The recent introduction of strain and strain rate echocardiography using tissue Doppler imaging has provided an
objective means to quantify global and regional left and right ventricular function.4–6 Tissue Doppler imaging has been useful in identifying left ventricular dyssynchrony in patients with HF who may benefit from cardiac resynchronization therapy.7–9 However, little is known regarding right ventricular mechanical activation and whether right ventricular dyssynchrony exists in patients with HF. Recent data have shown that right ventricular dyssynchrony is not only present in patients with pulmonary arterial hypertension and preserved left ventricular function, but that it also significantly correlates with global right ventricular function.10 The aim of this study was to use longitudinal strain imaging in patients with HF to determine if right ventricular dyssynchrony is present in these patients.
From the Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Manuscript received October 3, 2005; revised manuscript received February 5, 2006; revised manuscript accepted February 15, 2006. Reprint requests: Angel Lo´pez-Candales, MD, FACC, FASE, University of Pittsburgh Medical Center, Cardiovascular Institute, Scaife Hall 560, 200 Lothrop Street, Pittsburgh, PA 15213-2582. 1071-9164/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2006.02.008
Methods Patient Population Clinical and echocardiographic data were retrospectively obtained on 34 patients (mean age 56 6 13 years; 30 males) with a clinical history of HF and documented left ventricular ejection fraction #35% who underwent a standard transthoracic echocardiogram with tissue Doppler imaging. All patients had adequate
263
264 Journal of Cardiac Failure Vol. 12 No. 4 May 2006 visualization of the right ventricular free wall and the left ventricular lateral wall in addition to the interventricular septum. Patients with prosthetic valves, a pacer or defibrillator wire in the right ventricle, or a history of cardiac transplantation were all excluded. The study protocol was approved by the University of Pittsburgh Institutional Review Board.
Transthoracic Echocardiography All patients underwent a complete transthoracic echocardiogram including 2-dimensional, color flow, and spectral Doppler as well as tissue Doppler imaging using a GE-Vingmed Vivid 7 system (GE Vingmed Ultrasound, Horten, Norway). Standard 2dimensional echocardiographic evaluation of left and right ventricular size and function was performed. Right ventricular enddiastolic (RVEDA) and end-systolic areas (RVESA) were measured from the apical 4-chamber view to calculate right ventricular fractional area change [RVFAC 5 (RVEDA – RVESA) / RVEDA) 3 100].11 Peak pulmonary artery systolic pressures were estimated by calculating the systolic pressure gradient between the right ventricle and right atrium by the maximum velocity of the tricuspid regurgitant jet using the modified Bernoulli equation, and then adding to this gradient an estimated right atrial pressure based on the size of the inferior vena cava and its variation with respiration.12 Color-coded tissue Doppler cine loops were obtained as routinely performed in our echocardiography laboratory from 3 beats obtained in the apical 4-chamber view at the depths of 14 6 2 cm with pulse repetition frequency set at 1 kHz, Nyquist velocity range 616 cm/second, and frame rates 99 6 9 Hz. Initial length for longitudinal strain assessment was set at 12 mm and regions of interest (20 6 2 mm by 7 6 1 mm) were placed in the basal and mid-ventricular segments of the right ventricular free wall, interventricular septum, and left ventricular lateral wall. For each of the 3 regions, the basal and mid-ventricular measurements were averaged together. Right ventricular mechanical dyssynchrony was defined as the difference in time to peak strain between right ventricular free wall and ventricular septum. Left ventricular lateral wall dyssynchrony was determined as the difference in time to peak strain between the left ventricular lateral wall and the septum. Interventricular dyssynchrony was defined as the difference in time to peak strain between the right ventricular free wall and the left ventricular lateral wall, with a positive value indicating delay of the left ventricular lateral wall compared to the right ventricle.10,13,14
Results Patient Characteristics
Table 1 summarizes major clinical and echocardiographic characteristics. The study population was predominantly male with a mean New York Heart Association class of 2.7 6 0.9. Class 3 and 4 patients consisted the majority of the population (21 patients; 62%), with only 4 patients in New York Heart Association class 1. Mean QRS duration was 124 6 30 ms with 17 patients having QRS duration greater than 120 ms: 10 patients with a complete left bundle branch block morphology and 7 with a right bundle branch block. We were able to obtain a reliable tricuspid regurgitation signal in 30 of the 34 patients to estimate peak pulmonary artery systolic pressure; in the other 4 patients, the tricuspid regurgitation signal was too faint. Endocardial border resolution was adequate in all studies; therefore, we were able to obtain RVFAC in all 34 patients (mean RVFAC 32 6 12%). Strain Analysis
Although the peak longitudinal systolic strain in the interventricular septum was –9.8 6 5.2% and –8.4 6 4.6% in the left ventricular lateral wall, the peak systolic strain was significantly greater in the right ventricular free wall (–18.4 6 4.7%; P ! .001) compared with the other 2 regions. The time to peak longitudinal strain corrected for heart rate in the interventricular septum was 354 6 57 ms and was significantly delayed both in the right ventricular free wall (414 6 49 ms; P ! .001) and in the left ventricular lateral wall (434 6 71 ms; P ! .001). Mean right ventricular dyssynchrony for the entire study population was 59 6 45 ms and mean left ventricular lateral wall dyssynchrony was 80 6 62 ms. Figure 1 shows representative examples of strain imaging of the right ventricular free wall and interventricular septum in 2 patients with HF. Univariate analysis of right ventricular dyssynchrony with clinical and other echocardiographic variables was performed (Table 2). We found a strong correlation between right ventricular dyssynchrony and peak pulmonary artery systolic pressure (r 5 0.73; P ! .001) as shown in Fig. 2. Table 1. Clinical and Echocardiographic Characteristics of 34 HF Patients Characteristics
Statistical Analysis All echocardiographic parameters were calculated using the commercially available software EchoPAC PC version 3.00 (GE Vingmed Ultrasound) and determined by a single observer. All intervals were corrected for heart rate (corrected interval 5 measured interval/[RR interval]1/2).15,16 Group data (mean 6 standard deviation) were compared using the 2-tailed Student’s t-test for paired and unpaired data. Univariate analysis of right ventricular dyssynchrony to various echocardiographic and clinical variables was performed. A P value of !.05 was considered statistically significant.
Mean age Male gender New York Heart Association class Etiology Ischemic Idiopathic QRS duration (ms) LV ejection fraction (%) LV end-diastolic diameter (mm) Peak pulmonary artery systolic pressure (mm Hg) Right ventricular end-diastolic area (cm2) Right ventricular end-systolic area (cm2) Right ventricular fractional area change (%)
Results n 5 34 56 6 13 30 (88%) 2.7 6 0.9 15 (44%) 19 (56%) 124 6 30 22 6 7 63 6 9 46 6 15 26 6 9 19 6 9 32 6 12
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Fig. 2. Strong positive correlation between right ventricular dyssynchrony and peak pulmonary artery systolic pressure in 30 heart failure patients with measurable pulmonary artery pressures.
Fig. 1. A tissue Doppler image demonstrating (A) synchronized time to peak longitudinal strain of the right ventricular free wall (green curve) and the ventricular septum (yellow curve) in a HF patient with normal pulmonary artery pressures and (B) delayed time to peak longitudinal strain of the right ventricular free wall compared to the septum in a heart failure patient with pulmonary hypertension.
A weaker negative correlation between right ventricular dyssynchrony and RVFAC (r 5 –0.43; P ! .02) is shown in Fig. 3. Those patients with moderate or severe right ventricular dysfunction (RVFAC !30%; n 5 15) had significantly greater right ventricular dyssynchrony than the rest of the study population (79 6 44 ms vs. 43 6 41 ms; P ! .02). There was no significant correlation between right ventricular dyssynchrony and QRS duration or between right ventricular dyssynchrony and left ventricular dyssynchrony.
There was no difference in right ventricular dyssynchrony between the ischemic and nonischemic groups, although the groups were not equally represented. Despite having similar peak pulmonary artery systolic pressures (51 6 21 vs. 45 6 14 mm Hg) and RVFAC (30 6 7% vs. 32 6 13%) compared with the rest of the population, patients with right bundle branch block (n 5 7) had greater right ventricular dyssynchrony (86 6 45 ms) than the rest of the population (52 6 44 ms), but this did not reach statistical significance (P 5 .08). Mean interventricular dyssynchrony was 21 6 76 ms with a range from –95 ms to 183 ms. Twelve patients had interventricular dyssynchrony greater than 50 ms, indicating delay of the left ventricular lateral wall compared with the right ventricular free wall; and 7 patients had interventricular dyssynchrony of –50 ms and lower, indicating delay of the right ventricular free wall compared with the left ventricular lateral wall. There was no relationship between interventricular dyssynchrony and RVFAC, peak pulmonary artery systolic pressure, or QRS duration. Discussion This study is the first to depict changes in right ventricular mechanical synchrony in HF patients using strain
Table 2. Univariate Analysis of Right Ventricular Dyssynchrony to Other Clinical and Echocardiographic Variables in HF Patients Variable Age (years) QRS duration (ms) Peak pulmonary artery systolic pressure (mm Hg) Right ventricular end-diastolic area (cm2) Right ventricular end-systolic area (cm2) Right ventricular fractional area change (%) Left ventricular ejection fraction (%) Left ventricular end-diastolic diameter (mm) Right ventricular free wall peak strain (%)
r Value 0.07 0.26 0.73 0.41 0.42 –0.43 0.14 0.34 0.14
P value NS NS !.001 !.02 !.02 !.02 NS NS NS
Fig. 3. Significant negative correlation between right ventricular dyssynchrony and right ventricular fractional area change in all 34 patients.
266 Journal of Cardiac Failure Vol. 12 No. 4 May 2006 imaging echocardiography. We found that in these patients, right ventricular dyssynchrony correlates strongly with peak pulmonary artery systolic pressure and exhibits a negative correlation with global right ventricular function as represented by RVFAC. These findings suggest that, in addition to the presence of left ventricular dyssynchrony, which has been observed in patients with HF, there is also a disturbance of electromechanical coupling within the right ventricle that may contribute to the overall mechanical dyssynchrony seen in patients with HF. We found no correlation between right ventricular dyssynchrony and QRS duration. This is not particularly surprising given that left ventricular dyssynchrony has been reported even with a normal QRS duration.17 HF patients with right bundle branch block have been shown to exhibit left ventricular dyssynchrony,18 but the presence of right ventricular dyssynchrony has not been studied. With right bundle branch block, it would be expected that the magnitude of right ventricular dyssynchrony would be greater given that the free wall of the right ventricle undergoes delayed activation. The result is that much of the right ventricle undergoes activation after activation of the left ventricle has been completed.19,20 We did find that HF patients with right bundle branch block had greater right ventricular dyssynchrony than the rest of the population, despite similar degrees of pulmonary hypertension and global right ventricular function, but the number of patients in this study with right bundle branch block was too small to permit definitive conclusions. Because recent data suggest that about 30% of patients treated with cardiac resynchronization therapy do not show any clinical improvement,21 refinement of the selection process for biventricular pacing is crucial. The presence of right ventricular dyssynchrony may be a possible explanation to account for a significant number of nonresponders to resynchronization therapy. Clinical variables such as ischemic heart disease and a severely dilated left ventricle have been implicated as causes of a lack of response to resynchronization.21,22 However, attention has not been given to measures of right ventricular function. Studies have demonstrated that right ventricular dysfunction is a predictor of worse outcomes in patients with left ventricular dysfunction, so it would not be surprising if abnormalities in right ventricular mechanical activation contribute to the lack of response to resynchronization therapy. It is possible that interventricular dyssynchrony caused by the delay of the right ventricular free wall may not improve with biventricular pacing. Future studies are necessary to determine whether right ventricular dyssynchrony is prevalent in HF patients who are nonresponders to resynchronization. One important question that remains to be answered is whether the presence of right ventricular dyssynchrony should influence the site of right ventricular lead placement in HF patients referred for biventricular pacing. Unfortunately, there are limited sites in the right ventricle to consider for placement of a pacing wire, which can be stable
without the risk of mechanical perforation. In addition, although much research has focused on the left ventricle, little is known regarding right ventricular activation patterns in the presence of pacing in HF patients. Further prospective data analysis is necessary to assess the impact of pacing on improving right ventricular dyssynchrony and function. We recognize that the lack of outcome data and the small number of patients to permit definitive conclusions regarding right bundle branch block are limitations of this study. In addition, we did not obtain invasive pressure measurements; therefore, assessments of right ventricular timepressure plots, dp/dt, and pulmonary vascular resistance were not available. Global right ventricular function was assessed in this study via fractional area change from the 4chamber view. Although RVFAC has been used in previous studies for assessing global right ventricular function,23,24 it is nevertheless dependent on image quality.25 Three patients with atrial fibrillation were included in the study population. Although all time intervals were corrected for heart rate, we acknowledge that the beat-to-beat variations in filling and contraction may affect assessment of dyssynchrony. Finally, it is possible that in some patients the development of pulmonary hypertension and right ventricular dyssynchrony may have been a consequence of pulmonary disease undiagnosed at the time of the echocardiogram as opposed to HF. Our present findings suggest that patients with HF exhibit right ventricular dyssynchrony in addition to left ventricular dyssynchrony. Although right ventricular dyssynchrony was correlated with increasing pulmonary hypertension, a direct cause and effect is beyond the scope of this study, and further studies are needed to determine the sequence of events leading to right ventricular dyssynchrony and the effect of dyssynchrony on clinical outcomes. Furthermore, it is important to determine the effect of cardiac resynchronization therapy on right ventricular dyssynchrony in HF patients.
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