http://www.jhltonline.org

ORIGINAL CLINICAL SCIENCE

Electrical and mechanical dyssynchrony in pediatricpulmonary hypertensionAllison C. Hill, MD, Dawn M. Maxey, BS, David N. Rosenthal, MD,Stephanie L. Siehr, MD, Seth A. Hollander, MD, Jeffrey A. Feinstein, MD, andAnne M. Dubin, MD

From the Department of Pediatrics, Division of Cardiology, Stanford University Medical School, Palo Alto, California.

BACKGROUND: Electrical and mechanical dyssynchrony are often seen in patients with left ventricularfailure. In pediatric pulmonary hypertension (PH), right ventricular failure predominates; however, theprevalence of electrical and/or mechanical dyssynchrony in these patients is unknown. We examinedthe prevalence of electrical and mechanical dyssynchrony in pediatric PH patients.METHODS: Medical records (including, functional status, electrocardiograms and echocardiograms) ofpediatric PH patients were reviewed. QRS duration z-scores were calculated to determine electrical dys-synchrony. Echo vector velocity imaging was used to calculate the mechanical dyssynchrony index (DI).RESULTS: Seventy-seven PH patients (idiopathic pulmonary arterial hypertension [IPAH]: n � 26;congenital heart disease: n � 41; other: n � 10) were studied. Electrical dyssynchrony was seen in 84%(p � 0.01 vs historic controls), with a mean z-score of 4.3 (95% CI 3.5 to 5.1). There was no differencebetween those with IPAH, z � 3.6 (95% CI 2.5 to 4.6), and those without, z � 4.7 (95% CI 3.6 to 5.8).Mechanical dyssynchrony was seen in 76% of patients (mean DI � 66 � 47 vs 18 � 8 millisecondsin historic controls, p � 0.01) in both IPAH and non-IPAH patients. Post-operative congenital heartdisease patients had the largest dyssynchrony index. No correlation was found among electrical ormechanical dyssynchrony, hemodynamics or disease severity.CONCLUSIONS: Significant electrical and mechanical dyssynchrony is present in pediatric PH pa-tients, regardless of etiology. The overall effect of electrical and mechanical dyssynchrony on outcomesin this patient population is still unknown. Select patients may benefit from resynchronization therapy.J Heart Lung Transplant 2012;31:825–30© 2012 International Society for Heart and Lung Transplantation. All rights reserved.

KEYWORDS:pulmonaryhypertension;dyssynchrony;pediatric;ECG;TDI

Adults with left-sided heart failure have electrical dyssyn-chrony, and a progressive increase in QRS duration is associatedwith poor prognosis.1 In select patients, cardiac resynchronizationtherapy (CRT) improves acute ventricular mechanics, symptoms,morbidity and mortality.2–7 In children with tetralogy of Fallot andpulmonary regurgitation, diastolic dysfunction and right ventricu-lar (RV) enlargement have been shown to correlate with QRSprolongation, and resynchronization of the right ventricle has beenshown to improve hemodynamics.8–18 Similarly, adults with pul-

Reprint requests: Anne M. Dubin, MD, Department of Pediatrics,Lucile Packard Children’s Hospital, Stanford University Medical School,750 Welch Road, Suite 325, Palo Alto, CA 94306. Telephone: 650-723-7913. Fax: 650-725-8343.

E-mail address: amdubin@stanford.edu

1053-2498/$ -see front matter © 2012 International Society for Heart and Lunghttp://dx.doi.org/10.1016/j.healun.2012.04.004

monary hypertension (PH) may develop right ventricular failureand are known to have mechanical dyssynchrony that correlatesboth with disease severity and mortality, but this has not beenshown in children.19,20 We hypothesized that pediatric PH patientshave electrical and mechanical dyssynchrony, and that electricaland mechanical dyssynchrony correlate with disease severity.

Methods

Study population

A total of 80 pediatric patients (0 to 18 years old) with catheter-

ization-confirmed diagnosis of PH (mean pulmonary artery pres-

Transplantation. All rights reserved.

826 The Journal of Heart and Lung Transplantation, Vol 31, No 8, August 2012

sure �25 mm Hg and pulmonary vascular resistance �3 Woodsunits) between January 2003 and December 2011 were identifiedfrom the database at the Vera Moulton Wall Center for Pulmo-nary Vascular Disease at Stanford/Lucile Packard Children’sHospital. Three patients had pacemakers and were excludedfrom the study. Clinical data, were obtained, including diagno-ses, surgical history, World Health Organization (WHO) func-tional status, medications, 6-minute walk test distance(6MWT), electrocardiograms (ECGs), hemodynamic measure-ments from cardiac catheterization (mean right atrial pressure,right ventricular end-diastolic pressure, mean pulmonary arte-rial pressure, cardiac index, pulmonary vascular resistance andpulmonary capillary wedge pressure), b-type natriuretic peptide(BNP) and echocardiograms. The Dana Point classification sys-tem was used to group patients into an idiopathic PAH (IPAH)or non-idiopathic PH (non-IPAH) category.21

Study data were collected and managed using REDCap (Re-search Electronic Data Capture) electronic data capture toolshosted at Stanford University.22 Stanford’s institutional reviewboard approved the study and informed consent was obtained fromall patients.

Electrical dyssynchrony

Each patient had multiple ECGs interpreted: one at presentation ofPH symptoms; one just prior to starting intravenous therapy withepoprostenol or treprostinil when applicable; and one from themost recent clinic visit. Data from the most recent ECGs were usedfor correlations. All ECGs were recorded at a speed of 25 mm/sand were evaluated by two independent observers. QRS durationwas measured in multiple leads and compared with historic con-trols (Table 1).23 The z-scores were employed when comparingQRS durations among patients, as there was a wide age rangerepresented (7 months to 18 years) and this measurement is age-dependent. Dyssynchrony was defined as a z-score �2 when com-pared with historic controls.

Echocardiography

Echocardiographic images were reviewed by an investigator blindedto the clinical, ECG or hemodynamic information. Echocardiograms

Table 1 Historic Control Data for QRS Duration andMechanical Dyssynchrony Indices (MDI)23,25

Historic controls

QRSduration(ms)/MDI(ms)

Standarddeviation(ms)

HistoricN

ECG measurements(QRS duration)1–3 years 60 5 3563–8 years 70 5 3568–12 years 70 10 356

Echocardiographicmeasurements(MDI)3–5 years 14 7 236–10 years 16 5 1911–14 years 18 7 2915–18 years 22 9 27

were included if performed within 6 months of the most recent ECG,4-chamber views were obtained, and clear RV endocardial borderswere present for speckle tracking. Echo images were analyzed on avector velocity imaging (Syngo; Siemens, Medical Solutions, Moun-tain View, CA) workstation using a 2-beat 2-dimensional (2D) digitalclip including the apical 4-chamber view of the RV (average framerate 43 � 18 Hz). Longitudinal strain, time-to-peak strain, strain rateand time-to-peak strain rate were determined by tracing the RVendocardium starting and ending at the tricuspid valve annulus (Fig-ure 1). A mechanical dyssynchrony index (DI) was calculated basedon the standard deviation of time to peak strain at 4 points (excludingapical points) and compared with historic controls (Table 1).24,25

Intraobserver variability for the dyssynchrony index (DI) was deter-mined by remeasurement after a 10-week interval by a single ob-server. The correlation coefficient for intraobserver variability of DI(n � 10) was 0.7.

Statistical analysis

Data were analyzed using STATA software. QRS z-score wascompared between categorical groups (gender, intravenoustherapy, WHO class, current status, Dana Point classification,history of congenital heart disease and history of cardiac sur-gery) by Wilcoxon’s rank sum test. Univariate regression wasused to correlate QRS z-score with continuous variables (6-minute walk test, BNP, hemodynamic data and dyssynchronyindex). p � 0.05 was considered significant.

Results

A total of 77 patients with PH with a mean age of 10 � 6years were included. Patients’ age ranged from 7 months to18 years. Mean time since PH diagnosis was 4 � 3 years.Patients’ characteristics are shown in Table 2. Disease se-verity was varied with almost half of the patients in WHOFunctional Class III or IV status, 34% on intravenous ther-apy (treprostinil or epoprostenol), and 14% had either re-ceived a transplant or died. Twenty-six patients (34%) had

Figure 1 Sample VVI data showing the right ventricle with anapical view in a PH patient. The individual lines show the velocityfrom a specific RV location plotted against time.

IPAH, whereas 51 (66%) were non-IPAH patients. The

827Hill et al. Dyssynchrony in Pediatric Pulmonary Hypertension

majority (80%) of non-IPAH patients had congenital heartdisease (CHD) and 10 (20%) had other causes of PH,including chronic lung disease, portosystemic shunts, vas-culopathies or rheumatologic disorders. Intracardiac surgeryhad been performed in 27 patients (35%).

Electrical dyssynchrony was present in 84% of patientswhen compared with normal controls (p � 0.05). BothIPAH and non-IPAH patients had electrical dyssynchrony,

Table 2 Patients’ Characteristics

n (%)

Total 77(100)Male 38 (49)Age (years) 10 � 66-minute walk test (meters) 641 � 218Intravenous therapy 26 (34)WHO functional class

I or II 42 (55)III or IV 35 (45)

Transplanted or deceased 11 (14)Dana Point classification

IPAH 26 (34)Non-IPAH 51 (66)Congenital heart disease 41 (53)History of intracardiac surgery 27 (35)

IPAH, idiopathic pulmonary artery hypertension; non-IPAH, non-idiopathic pulmonary artery hypertension.

Figure 2 Breakdown of pulmonary hypertension patients andpresence of electrical dyssynchrony by type. IPAH, idiopathicpulmonary hypertension; CHD, congenital heart disease; E-DYS,electrical dyssynchrony.

Table 3 Echocardiographic Variables and Dyssynchrony Index

Longitudinalstrain (%)

Time-to-peakstrain (ms)

All patients –16.3 � 6.1 368.2 � 148IPAH –17.1 � 6.6 358.3 � 111Non-IPAH –15.5 � 5.7 376.2 � 174CHD –14.6 � 5 393.3 � 188No CHD –19.7 � 7.1 304 � 67.8Surgery –14.2 � 5.5 353.1 � 128.8No surgery –15.2 � 4.4 473.7 � 265.6

Data expressed as average � standard deviation. All variables exclu

with no significant difference between these groups (p �0.2) (Figure 2). For all patients, the mean z-score was 4.3(confidence interval 3.5 to 5.1).

QRS duration z-scores and 95% confidence intervals(CIs) are shown in Figure 3. Post-operative CHD patientshad significantly higher z-scores than those who did nothave a history of cardiac surgery (p � 0.004). No significantdifferences in z-scores were found when comparing differ-ent types of congenital heart disease. There were poor cor-relations between electrical dyssynchrony z-score and age,hemodynamic measurements (including pulmonary arterypressures and pulmonary vascular resistance) and clinicalseverity. No significant difference in QRS z-score was seenafter initiation of intravenous (IV) drug therapy (averagez-score � 3.3 prior to IV therapy vs 4.0 after initiation of IVtherapy, p � non-significant).

Forty-seven of the total 77 patients had vector velocityimaging (VVI) data available, although the quality of theechocardiographic images varied (29 excellent, 16 reason-able, 2 difficult to trace borders). Seventy-six percent of allpatients with VVI data had mechanical dyssynchrony whencompared with normal historic controls (p � 0.01).25 Echo-cardiographic variables, including longitudinal strain andtime-to-peak strain are shown in Table 3. No significantdifferences were found between IPAH and non-IPAH, CHDor surgery patients for any echocardiographic variable. The

Figure 3 Patient characteristics and QRS duration z-scores (vshistoric controls) with 95% confidence intervals. A significantdifference between CHD patients with and without surgery wasfound (*p � 0.05).

Strain rate(/s)

Time-to-peakstrain rate (ms)

Dyssynchronyindex (ms)

–1.2 � 0.5 257.7 � 238.3 66.4 � 47.1–1.3 � 0.4 211.9 � 125.3 69.2 � 42.9–1.2 � 0.5 294 .7 � 297.9 64.2 � 51–1.1 � 0.3 289.3 � 280.2 70.2 � 54.9–1.6 � 0.8 317.2 � 401.8 39.2 � 13.5

–1 � 0.4 312.9 � 337.5 76.3 � 64.9–1.1 � 0.3 242 � 104.7 58 � 26.1

. No significant differences between groups were found.

de apex

828 The Journal of Heart and Lung Transplantation, Vol 31, No 8, August 2012

mean mechanical DI for all patients was 66 � 47 millisec-onds. Figure 4 shows the mean DI and 95% confidenceintervals broken down by patient characteristics. There wasno significant difference between DI in patients with IPAHvs non-IPAH. Of the patients with non-IPAH, those withCHD trended toward a higher average DI compared withthose without CHD (70 � 54.9 vs 39 � 13.5 milliseconds,respectively, p � 0.08). There was no difference betweenpost-operative CHD patients and those who had not hadcardiac surgery (76 � 65 vs 58 � 26 milliseconds, respec-tively, p � 0.2). No differences in DI were found whencomparing different types of CHD (Table 4). No differencein the level of mechanical dyssynchrony was seen whencomparing patients with normal QRS duration vs those withevidence of electrical dyssynchrony (DI � 59 � 53 vs 68 �46 milliseconds, respectively, p � 0.5). There was no cor-relation (R2 � 0.1) between mechanical and electrical dys-synchrony.

Discussion

Adult patients with left-sided CHF often have electricaldyssynchrony that contributes to their poor hemodynamics,and this is associated with increased mortality.1 Abnormalventricular activation causes a discoordinate contractionpattern that then induces a cascade of systolic and diastolichemodynamic abnormalities and a deterioration in pumpfunction over time.26 Inter- and intraventricular dyssyn-chrony can lead to either delayed or prolonged relaxationtimes resulting in decreased ejection fraction or filling time.In patients with left ventricular failure and left bundlebranch block, cardiac resynchronization therapy via abiventricular pacemaker, has produced acute hemodynamicimprovement in left ventricular performance.7,27 Multiplestudies have shown that chronic resynchronization therapyimproves symptoms, exercise performance and even mor-tality in this population.2,28,29

Patients with tetralogy of Fallot and RV volume overload

Figure 4 Characteristics of patients and mechanical dyssyn-chrony with average dyssynchrony index and 95% confidenceintervals. Normal patients without heart disease have a dyssyn-chrony index of 18 � 8 milliseconds.

also have electrical dyssynchrony that correlates with an

increased risk of sudden death.8–14 Gatzoulis and colleaguesfirst described an association between QRS duration �180milliseconds, increased right ventricular size and increasedrisk of life-threatening ventricular arrhythmias.8,14 The re-lationship of QRS duration to RV mechanics was furtherelucidated by Uebing and colleagues, who showed a delayin onset of contraction of the RV free wall in patients withrepaired tetralogy of Fallot and right bundle branch block.10

They were able to correlate the severity of delay withduration of the surface QRS complex, suggesting a possiblerole for resynchronization in right-sided heart failure.

Patients with pulmonary hypertension often have bothpressure (due to increased pulmonary vascular resistance)and volume overload (due to pulmonary regurgitation), re-sulting in decreased RV function, which in other patientpopulations has been associated with mechanical and/orelectrical dyssynchrony.19,20 In our study, both mechanicaland electrical dyssynchrony were seen in the majority of ourpediatric PH patients, regardless of etiology, disease sever-ity or duration of disease. The degree of electrical andmechanical dyssynchrony was not associated with tradi-tional measures of disease severity.

Not surprisingly, electrical dyssynchrony was most no-table in patients with CHD, and was significantly increasedin those who underwent repair compared with those notrepaired. This dyssynchrony may reflect increased RV vol-ume load, which is not entirely unexpected if one extrapo-lates from the tetrology of Fallot experience.

In adults with LV failure, baseline QRS prolongation isa good indicator of subsequent improvements in hemody-namics and quality of life after CRT.2,5–7,30,31 CRT has notbeen nearly as well studied in the congenital heart diseasepopulation. However, resynchronization therapy has beenshown to improve hemodynamics in select pediatric patientswith repaired tetralogy of Fallot, RV failure and QRS pro-longation.15–17 We demonstrated acute hemodynamic im-provement in patients with tetralogy of Fallot and right-sided heart failure with temporary right ventricularpacing.15 RV resynchronization resulted in an improvedcardiac index by 18% and RV dP/dT by 22%.

Even more preliminary are studies on CRT in the settingof PAH. A PAH animal model demonstrated improvementin RV function after RV pacing.32 In a case report of anadult with severe PAH and QRS prolongation, CRT led toimproved symptoms, increased cardiac output and de-creased pulmonary vascular resistance.33 In our own prac-tice, we have anecdotal evidence of this improvement aswell. As our study has demonstrated that electrical dyssyn-chrony is present in a large proportion of PAH patients,CRT may be a successful therapeutic option for improvinghemodynamics and quality of life.

Although this is the first pediatric study to evaluate thepresence of mechanical and electrical dyssynchrony in PHpatients, there have been several studies that have assessedboth measures in the adult PH population. Sun and col-leagues correlated QRS prolongation with clinical severity,but found only 16% of patients had a QRS duration of �120

milliseconds.34 This finding is quite different from ours,

829Hill et al. Dyssynchrony in Pediatric Pulmonary Hypertension

which showed �80% of patients having evidence of QRSprolongation. At this time, the reasons for these differencesare unclear, but may be related to underlying etiology anddisease presentation.

As in adult studies of PH, we found a significant degreeof mechanical dyssynchrony as measured by echocardio-gram in PH patients, both idiopathic and non-idiopathic.Interestingly, there was no correlation between mechanicaldyssynchrony and electrical dyssynchrony in these patients,making interpretation of the data difficult, which raisesquestions of what the mechanical dyssynchrony indices aremeasuring and how best to interpret abnormal mechanicalactivation in these patients. Kass and colleagues noted thatmechanical dyssynchrony may be found in anywhere be-tween 30% and 70% of adult heart failure patients and maynot reflect a delay in electrical activation but rather theheterogeneity of contractile properties of the ventricularwall.35 Our study supports this theory and thus it may bedifficult to interpret the relationship between electrical andmechanical dyssynchrony in this population.

The current study is limited by its retrospective design,homogeneous patient population, imperfect cardiac cathe-terization and limited RV VVI data. Nevertheless, we foundthat electrical dyssynchrony and mechanical dyssynchronyexist in pediatric patients with idiopathic and non-idiopathicPH, and that electrical dyssynchrony is significantly asso-ciated with history of intracardiac surgery. Our findingssupport the need for further studies using other diagnosticmodalities, such as magnetic resonance imaging, to furtherassess dyssynchrony and determine whether CRT has a rolein select pediatric patients with PH.

Disclosure statementThe authors have no conflicts of interest to disclose.

References

1. Kashani A, Barold SS. Significance of QRS complex duration in

Table 4 Breakdown of Electrical and MechDisease

Type of CHDNumber ofpatients

Npwd

VSD 18TOF/TOF variant 6PDA 6Other 11Total 41 2

No significant differences were found between garteriousus; TOF, tetralogy of Fallot; VSD, ventricu

patients with heart failure. J Am Coll Cardiol 2005;46:2183-92.

2. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronizationtherapy with or without an implantable defibrillator in advancedchronic heart failure. N Engl J Med 2004;350:2140-50.

3. Beshai JF, Grimm RA, Nagueh SF, et al. Cardiac-resynchronizationtherapy in heart failure with narrow QRS complexes. N Engl J Med2007;357:2461-71.

4. Chung ES, Leon AR, Tavazzi L, et al. Results of the predictors ofresponse to CRT (PROSPECT) trial. Circulation 2008;117:2608-16.

5. Abraham WT. Cardiac resynchronization therapy. Prog CardiovascDis 2006;48:232-8.

6. Cleland JG, Daubert JC, Erdmann E, et al. Longer-term effects ofcardiac resynchronization therapy on mortality in heart failure [theCArdiac REsynchronization-Heart Failure (CARE-HF) trial extensionphase]. Eur Heart J 2006;27:1928-32.

7. Kass DA, Chen CH, Curry C, et al. Improved left ventricular mechan-ics from acute VDD pacing in patients with dilated cardiomyopathyand ventricular conduction delay. Circulation 1999;99:1567-73.

8. Gatzoulis MA, Balaji S, Webber SA, et al. Risk factors for arrhythmiaand sudden cardiac death late after repair of tetralogy of Fallot: amulticentre study. Lancet 2000;356:975-81.

9. Abd El Rahman MY, Abdul-Khaliq H, Vogel M, et al. Relationbetween right ventricular enlargement, QRS duration, and right ven-tricular function in patients with tetralogy of Fallot and pulmonaryregurgitation after surgical repair. Heart 2000;84:416-20.

10. Uebing A, Gibson DG, Babu-Narayan SV, et al. Right ventricularmechanics and QRS duration in patients with repaired tetralogy ofFallot: implications of infundibular disease. Circulation 2007;116:1532-9.

11. Marie PY, Marcon F, Brunotte F, et al. Right ventricular overload andinduced sustained ventricular tachycardia in operatively ”repaired”tetralogy of Fallot. Am J Cardiol 1992;69:785-9.

12. Wessel HU, Cunningham WJ, Paul MH, et al. Exercise performance intetralogy of Fallot after intracardiac repair. J Thorac Cardiovasc Surg1980;80:582-93.

13. Katz NM, Blackstone EH, Kirklin JW, et al. Late survival and symp-toms after repair of tetralogy of Fallot. Circulation 1982;65:403-10.

14. Gatzoulis MA, Till JA, Somerville J, et al. Mechanoelectrical interac-tion in tetralogy of Fallot. QRS prolongation relates to right ventricularsize and predicts malignant ventricular arrhythmias and sudden death.Circulation 1995;92:231-7.

15. Dubin AM, Feinstein JA, Reddy VM, et al. Electrical resynchronization: anovel therapy for the failing right ventricle. Circulation 2003;107:2287-9.

16. Dubin AM, Janousek J, Rhee E, et al. Resynchronization therapy inpediatric and congenital heart disease patients: an international multi-center study. J Am Coll Cardiol 2005;46:2277-83.

17. Janousek J, Tomek V, Chaloupecky VA, et al. Cardiac resynchroni-zation therapy: a novel adjunct to the treatment and prevention ofsystemic right ventricular failure. J Am Coll Cardiol 2004;44:1927-31.

18. Thambo JB, Dos Santos P, De Guillebon M, et al. Biventricular

Dyssynchrony by Type of Congenital Heart

r ofsI QRS

z-scoreDyssynchronyindex

4.5 � 2.5 78.2 � 42.46.7 � 3.1 23.6 � 33.32.5 � 1.7 43 � 29.76.5 � 6.4 82 � 96.35.2 � 4.0 70.2 � 54.9

CHD, congential heart disease; PDA, patent ductustal defect.

anical

umbeatientith VVata

84541

roups.lar sep

stimulation improves right and left ventricular function after tetralogy

830 The Journal of Heart and Lung Transplantation, Vol 31, No 8, August 2012

of Fallot repair: acute animal and clinical studies. Heart Rhythm2010;7:344-50.

19. Sachdev A, Villarraga HR, Frantz RP, et al. Right ventricular strain forprediction of survival in patients with pulmonary arterial hypertension.Chest 2011;139:1299-309.

20. Lopez-Candales A, Dohi K, Rajagopalan N, et al. Right ventriculardyssynchrony in patients with pulmonary hypertension is associatedwith disease severity and functional class. Cardiovasc Ultrasound2005;3:23.

21. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical clas-sification of pulmonary hypertension. J Am Coll Cardiol 2009;54(suppl):S43-54.

22. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture(REDCap)—a metadata-driven methodology and workflow processfor providing translational research informatics support. J BiomedInform 2009;42:377-81.

23. Davignon ARP, Boiselle E, Soumis F, et al. Normal ECG standard forinfants and children. Pediatr Cardiol 1979;1:123-34.

24. Rajagopalan N, Dohi K, Simon MA, et al. Right ventricular dyssyn-chrony in heart failure: a tissue Doppler imaging study. J Card Fail2006;12:263-7.

25. Hui W, Slorach C, Bradley TJ, et al. Measurement of right ventricularmechanical synchrony in children using tissue Doppler velocity andtwo-dimensional strain imaging. J Am Soc Echocardiogr 2010;23:1289-96.

26. Leclercq C, Gras D, Le Helloco A, et al. Hemodynamic importance ofpreserving the normal sequence of ventricular activation in permanent

cardiac pacing. Am Heart J 1995;129:1133-41.

27. Blanc JJ, Etienne Y, Gilard M, et al. Evaluation of different ventricularpacing sites in patients with severe heart failure: results of an acutehemodynamic study. Circulation 1997;96:3273-7.

28. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resyn-chronization and implantable cardioversion defibrillation in advancedchronic heart failure: the MIRACLE ICD Trial. JAMA 2003;289:2685-94.

29. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biven-tricular pacing in patients with heart failure and intraventricular con-duction delay. N Engl J Med 2001;344:873-80.

30. Nelson GS, Curry CW, Wyman BT, et al. Predictors of systolicaugmentation from left ventricular preexcitation in patients with di-lated cardiomyopathy and intraventricular conduction delay. Circula-tion 2000;101:2703-9.

31. Leclercq C, Cazeau S, Ritter P, et al. A pilot experience with perma-nent biventricular pacing to treat advanced heart failure. Am Heart J2000;140:862-70.

32. Handoko ML, Lamberts RR, Redout EM, et al. Right ventricularpacing improves right heart function in experimental pulmonary arte-rial hypertension: a study in the isolated heart. Am J Physiol Heart CircPhysiol 2009;297:H1752-9.

33. Healey JS, Davies RA, Tang AS. Improvement of apparently fixedpulmonary hypertension with cardiac resynchronization therapy.J Heart Lung Transplant 2004;23:650-2.

34. Sun PY, Jiang X, Gomberg-Maitland M, et al. Prolonged QRS dura-tion: a new predictor of adverse outcome in idiopathic pulmonaryarterial hypertension. Chest 2012;141:374-80.

35. Kass DA. An epidemic of dyssynchrony: but what does it mean? J Am

Coll Cardiol 2008;51:12-7.