11. Levine TB, Levine AB, Keteyian SJ, Narins B, Lesch M. Reverse remodeling C, Shelto B, for the SOLVD Investigators. Effects of long-term enalapril therapy in heart failure with intensification of vasodilator therapy. C/in Cardiol 1997;20: on cardiac structure and function in patients with left ventricular dysfunction: 697-702. results of the SOLVD echocardiography substudy. Circularion 1995;91:2573- 12. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in 2581. severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study. N Engl J Med 1987;316:1429-1435.

17. McDonald KM, Carlyle PF, Matthews I, Hauer K, Elbers T, Hunter D, Cohn

13. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Ttistani F, Smith R, JN. Early ventricular remodeling after myocardial damage and its attenuation

Dunkman WB, Loeb H, Wong M, et al. A comparison of enalapril with hydral- by converting enzyme inhibition. Trans Assoc Am Physicians 1990;103:229-

azine-isosorbide dinitrate in the treatment of chronic congestive heat failure. 235.

N Engl J Med 1991;325:303-310. 18. Nakashima Y, Fouad FM, Tarazi RC. Long-term captopril therapy in con-

14. The SOLVD Investigators. Effect of enalapril on survival in patients with gestive heart failure: serial hemodynamic and echocardiographic changes. Am

reduced left ventricular ejection fractions and congestive heart failure. N Eng[ Heart J 1982;104:827.

.I Med 1991;325:293-302. 19. Shimoyama H, Sabbah HN, Rosman H, Kono T, Alam M, Goldstein S.

15. Konstam MA, Rousseau MF, Kronenberg MW, Udelson JE, Melin J, Stewart Effects of long-term therapy with enalapril on severity of functional mitral

D, Dolan N, Edens TR, Ahn S, Kinan D, et al, for the SOLVD Investigators. regurgitation in dogs with moderate heart failure. J Am Co0 Cardiol 1995;25:

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progression of ventricular dysfunction in patients with heart failure. Circulation 20. Eichhom EJ, Bristow MR. Medical therapy can improve the biological 1992;86:431-438. properties of the chronically failing heart: a new era in the treatment of heart 16. Greenberg B, Quinones MA, Koilpillai C, Limacher M, Shindler D, Benedict failure. Circularion 1996;94:2285-2296,

Usefulness of Echocardiographie Determined Tricuspid Regurgitation in Predictin

(9 Event-Free Sunrival in

Severe Heart Failure Secon ary to Idiopathic-Dilated Cardiomyopathy or to lschemic Cardiomyopathy

Judy Hung, MD, Todd Koelling, MD, Marc J. Semigran, MD, G. William Dee, MD,

Robert A. Levine, MD, and Thomas G. Di Salvo, MD

T ricuspid regurgitation (TR) is often a consequence of right ventricular (RV) dilation and hypokine-

sia.’ The finding of TR may therefore provide an indirect measure of RV systolic dysfunction. The threefold purpose of the present study of patients with severe heart failure referred for cardiac transplant evaluation was to determine if echocardiographically detected TR is (1) associated with RV systolic dys- function, (2) predicts event-free survival, and (3) com- pares favorably in prognostic value to peak VO,.

. . . We reviewed the clinical and echocardiographic

data of 306 patients referred to our institution from 1985 to 1995 for evaluation for cardiac transplanta- tion. Of these 306 patients, 117 had technically ade- quate echocardiograms performed. These 117 patients comprise the study population.

Two-dimensional and color Doppler echocardiog- raphy were performed with a 2.5-MHz phased array sector scanner (Hewlett-Packard, 77020A, Andover, Massachusetts). TR was assessed in all standard views, including the parasternal short-axis, RV inflow, apical 4-chamber, and subcostal views. If no TR was seen in any view, then TR was considered absent. Trace, mild, moderate, and severe TR were defined by color Dopp- ler echocardiography as a TR jet area occupying <lo%, 10% to 20%, 20% to 33%, or >33% of the right atria1 area, respectively.2-4 Systolic flow reversal

From the Massachusetts General Hospital Heart Failure and Transplanta- tion Center, Harvard Medical School, Boston, Massachusetts. Dr. Di Salvo’s address is: MGH Heart Failure Center, Bigelow 628, Massachu- setts General Hospital, 55 Fruit St, Boston, Massachusetts 02 1 14 E-mail: disalvo.thomas@mgh.harvard.edu. Manuscript received December 16, 1997; revised manuscript received and accepted June 1.5, 1998.

01998 by Excerpto Medico, Inc. All rights reserved.

in the hepatic vein flow was considered to represent at least moderate TR.5

Before any analyses, patients were prospectively divided into 2 groups based on the presence or ab- sence of echocardiographic TR (TR+ and TR- groups, respectively). The TR+ group were patients with mild, moderate, or severe grades of TR by color Doppler echocardiography. The TR- group were pa- tients with either absent or trace grades of TR by color Doppler echocardiography.

RV dilation and hypokinesia were assessed quali- tatively in the apical 4-chamber view. In 48 patients with adequate echocardiographic views, RV function was assessed quantitatively by the percent RV area change (%RV area change) defined as (RV end-dia- stolic area - RV end-systolic area)/RV end-diastolic area.5 Area calculations were performed offline (Sony Medical Electronics, Parkridge, New Jersey) and av- eraged over 3 beats.

Sixty-one of the 117 patients (52%) also underwent cardiopulmonary exercise testing during transplant evaluation. All exercise testing was performed follow- ing an overnight fast without discontinuing oral med- ications. Upright symptom-limited cycle ergometry was performed on a bicycle ergometer (pedal-mode ergometer, Warren E. Collins, Inc.) at a constant cycle speed of 60 rpm using a continuous ramp protocol in which workload increased by 12.5 Wlmin up to peak exercise.6 Heart rate, blood pressure, and the 12-lead electrocardiogram were monitored continuously. Breath-to-breath respiratory gas exchange analysis was performed with a mouthpiece, nose clips, and a metabolic cart (2001 System, Medical Graphics Corp, St. Paul, Minnesota). Peak oxygen uptake (peak VO,) was defined as the highest VO, measured during the

0002.9149/98/$19.00 1301 PII SOOO2-9 149(98)00624-9

TABLE I Clinical Characteristics: Tricuspid Regurgitation Absent (TR-) and Tricuspid Regurgitation Present (TR+) I

TR-

(n = 42)

TR+

(n = 75) p Value

Age (yrs) 48% 12 492 12 0.7 Diagnosis (%)

Nonischemic 27 (23) 55 (47) 0.3 lschemic 15 (13) 20 (17)

New York Heart Association functional class (%)

II 9 (8) 8 171 0.2 Ill 23 (19) 41 (35)

PIk VO, (ml/kg/min) 12 9 (8) 24 27 1224 (23) 1.0

last minute of symptom-limited exercise and was cal- culated on-line as previously reported.7

After initial evaluation for transplantation, patients were followed every 3 to 6 months at the Massachu- setts General Hospital Heart Failure Center. Medical therapy was adjusted to achieve a maximally tolerated vasodilator dose, an edema-free state, and normal renal function whenever possible. Follow-up data were collected by review of Massachusetts General Hospital medical records and telephone interview of the referring physician, the patient, or’ the patient’s family. Follow-up information was available for all 117 patients at time of analysis.

ternal diameter at end-diastole and a higher prevalence of echocardiographic mitral regurgitation than the TR- group.

The presence of TR was strongly associated with RV dilation and hypokinesia: 82% of patients in the TR+ group had RV hypokinesia versus only 34% of patients in the TR- group. Similarly, 75% of patients in the TR+ group had RV dilation versus only 23% of patients in the TR- group.

Chi-square or Fisher’s exact tests were used for comparison of rates and proportions as appropriate. The Student’s t test, with assumption of unequal vari- ance, was used to compare the means of normally distributed continuous variables between groups. Be- fore any survival analyses, event-free survival was defined as freedom from either death (sudden death or progressive heart failure death) or pretransplant ad- mission for continuous inotropic or mechanical sup- port as a bridge to transplant. Any cardiac transplan- tation from home was considered a censored event. Survival between groups was compared by the Peto- Prentice log-rank test. Cox proportional hazards meth- ods were used for multivariate survival analysis. In all analyses, a p value CO.05 was considered statistically significant.

Percent RV area change was strongly associated with both qualitative RV function and TR. Table II shows the relation between 3 echocardiographic in- dexes of RV function (TR, RV dilation, RV hypoki- nesia) and echocardiographic %RV area change. The %RV area change was significantly lower in patients in which TR, RV hypokinesia, and RV dilation were present.

During a mean follow-up of 357 & 428 days, 65 of the 117 patients reached the combined end-point (56%). Thirty-two patients were admitted for contin- uous inotropic or mechanical support as a bridge to cardiac transplantation (28%) and 33 patients died (28%). For all 117 patients, event-free survival was significantly longer for the TR- patients (p = 0.002 by log-rank, Figure 1). Estimated l-year event-free survival in the TR- patients was 68% versus 30% in the TR+ patients.

The clinical characteristics of the 117 patients are shown in Table I. Of the 117 patients, 42 were TR-

The univariate and multivariate predictors of

(36%) and 75 were TR+ (64%). Comparison of the event-free survival in the 61 patients with complete

clinical characteristics between the TR- and TR+ clinical, echocardiographic, and cardiopulmonary ex- ercise data are shown in Table III. In univariate anal-

groups is shown in Table 1. There were no significant yses, gender, New York Heart Association functional differences between the TR- and TR+ groups with class, left ventricular end-diastolic internal diameter, respect to age, cause of heart failure, New York Heart and TR were predictors of event-free survival. In Association functional class, left ventricular ejection multivariate analysis, only New York Heart Associa- fraction, or peak VO,. The TR+ group had a signif- tion functional class and TR were selected as inde- icantly greater echocardiographic left ventricular in- pendent predictors.

TABLE II Percent Right Ventricular (RV) Area Change and RV Function

Absent Present p Value

TR 36~ 16 25 + 8 0.016 RV 472 10 24 f 8 0.0001 RV dilation 39% 15 23 ? 7 0.0001

TABLE Ill Predictors of Survival to the Combined End Point

Univariote

Age Gender

Diagnosis New York Heart Association functional class Peak VO, Left ventricular ejection fraction Left ventricular enddiastolic internol diometer

Mitral regurgitation TR Multivoriote

New York Heart Association functional class TR

p Value

0.15

0.02 0.58 0.005 0.69 0.06 0.02 0.1 1 0.002

0.02 0.002

1302 THE AMERICAN JOURNAL OF CARDIOLOGYa VOL 82 NOVEMBER 15, 1998

0.8

0.7

j 0.6

'; 0.5

; 0.4

0.3

0.2

0.1

OJ

0 20 40 63 80 100 120 140 Weeks

FIGURE 1. Echocardiagiaphic TR and evenbfree survival. The actuarial event-free sur- vival of the patients w$hout echocardiographic I? (diamonds) and the ‘ents with echocardiographic TR (squares) is shown. Event-free survival was signi R” cantly better for patients without echocardiiraphic TR. Log-rank: p = 0.002. (Mean follow-up: 357 f 428 days.)

. . .

The main finding of this study is that echocardio- graphic TR predicted worse event-free survival in patients with severe heart failure referred for cardiac transplant evaluation. In addition, echocardiographic TR ~5:s a reliable marker of RV systolic dysfunction. TR was strongly associated with 3 echocardiographic features of RV dysfunction, namely, RV dilation, RV hypokinesia, and lower %RV systolic area change. Because no patients had echocardiographic abnormal- ities of the tricuspid valve leaflets or structural appa- ratus or tricuspid valve prolapse, this suggests that TR is a marker for RV systolic dysfunction in patients with severe heart failure.

Previous studies have reported the prognostic im- portance of RV dilation and systolic function in severe heart failure.738 The results of the present study cor- roborate the findings of these previous studies that RV dilation and systolic dysfunction predicted worse sur- vival in patients with advanced left ventricular systolic dysfunction. The present study also extends these findings to a larger patient population.

This study is retrospective and observational. He- modynamics measured by right heart catheterization were not obtained at the time of echocardiography. Like other regurgitant lesions, TR may exhibit signif-

icant load dependence and variabil- ity in echocardiographic severity. The TR+ patients had a higher prevalence of mitral regurgitation and larger left ventricular end-dia- stolic internal diameter, and may thus have had a greater degree of reactive pulmonary hypertension than the TR- patients. Echocardio- graphic estimates of pulmonary ar- tery pressures were obtainable in only a small number of patients in the TR- group (8 of 42) due to the small size of the TR jet in those patients in whom TR severity was “trace.” Because of the small num- ber of patients in the TR- group with measurable estimated pulmo- nary artery systolic pressures, we did not compare pulmonary artery pressures between the TR- and TR+ groups.

In summary, we reviewed 2-di- mensional and color Doppler

echocardiographic data from 117 patients with ad- vanced symptomatic heart failure to determine if echocardiographic TR would predict RV function and event-free survival. The presence of echocar- diographic TR predicted RV dilation and dysfunc- tion and was associated with worse survival.

1. Sagie A, Schwammenthal E, Padial LR, Vasquez de Prada JA, Weyman AE. Levine RA. Determinants of Functional tricuspid regurgitation in incomplete valve closure: Doppler color flow study of IO9 patients. J Am Co// Curclinl 1994;24:446-53. 2. Chopra HK, Nanda NC, Fan I’. Can two-dimensional echocardiography and Doppler color flow mapping identify the need for tricuspid valve repair? J Am Cdl Cardiol 19X9:14:1266-1274. 3. Cooper JW, Nanda NC, Philpot EF, Fan P. Evaluation of valvular regurgitation by color Doppler. J Am Sot Echocwrdiogruphr 1989:X6- 66. 4. Mugge A. Daniel WG, Henmann G, Simon R. Lichtlen PR. Quantification of tricuspid regurgitation by Doppler color tlow mapping after cardiac transplant. Am J Cardiol 1990:66:884 887. 5. Kaul S, Tei C, Hopkins JM, Shah PM, Awssment of right ventricular function using two-dimensional echocardiography. Am Ikurt J lY84:107:.526-53 I. 6. Boucher C, Kanareck D, Okada R. Exercise testing in aortic regurgitation: comparison of radionuclide left ventricular ejection fraction fraction with exer- cise performance at the anacrohic threshold and at peak exercise. Arr! J Cardiol 1983;52:801-808. 7. Di Salvo TG, Math& 41, Semigran MJ, Dee GW. Preserved right ventricular ejection fraction predicts exercise capacity and survival in advanced heart failure. J Am Coil Curdiol 1995;25:1143 1153. 8. Polak JF, Holman BI., Wynne J, Colucci WS. Right ventricular ejection fraction: an indicator of increased mortality in patients with congestive heart failure associated with coronary artery disease. J .&?I Cbll Cm&/ 1983:2:217- 224.

NE’ REPORTS 1303