- Email: [email protected]
Prognostic Implications of Serial Assessments of Pulmonary Hypertension in Severe Chronic Heart Failure
Prognostic Implications of Serial Assessments of Pulmonary Hypertension in Severe Chronic Heart Failure Francesco Grigioni, MD, PhD,a Luciano Potena, MD, PhD,a Nazzareno Galiè, MD,a Francesco Fallani, MD,a Mauro Bigliardi, MD,a Fabio Coccolo, MD,a Gaia Magnani, MD, PhD,a Alessandra Manes, MD,a Andrea Barbieri, MD,b Alessandro Fucili, MD, PhD,c Carlo Magelli, MD,a and Angelo Branzi, MDa Background: It is unknown whether time-related changes of pulmonary hypertension (PH) have prognostic relevance in severe chronic heart failure (CHF). Methods: All CHF patients referred for follow-up from 1996 through 2003 were screened for this study. Eligibility depended on availability of a concomitant clinical, laboratory, electrocardiographic (ECG), echocardiographic and right-heart catheterization (RHC) assessment at index evaluation, as well as absence of pre-capillary PH. Results: One hundred ninety-six patients (age 54 ⫾ 9 years; 27% women, 73% men; 50% in New York Heart Association [NYHA] Class III or IV) were included. PH at index evaluation was an independent predictor of acute heart failure or cardiovascular death (AHF/CD), with adjusted risk ratio (RR) ⫽ 2.30, 95% confidence interval (CI) 1.42 to 3.73 and p ⬍ 0.001. A pre-study (ⱖ6 months) RHC was available for 174 of the 196 patients. Worsening of mean pulmonary artery pressure (mPAP) of ⱖ30% (a pre-specified cut-off corresponding to the 75th percentile of ⌬mPAP%) provided prognostic information independent of all index-evaluation parameters (adjusted RR ⫽ 2.60, 95% CI 1.45 to 4.67, p ⫽ 0.001), and from time-related changes in the other hemodynamic parameters (p ⱕ 0.033). Conclusions: PH retains independent prognostic significance even after adjusting for a large set of clinical/ laboratory/instrumental parameters. Furthermore, serial measurements of mPAP seem to provide additional prognostic information as compared with a single assessment. These findings indicate that serial evaluations of PAP may help identify a sub-set of high-risk CHF patients deserving a particularly close follow-up to facilitate timely indications for non-pharmacologic strategies, including (when appropriate) heart transplantation. J Heart Lung Transplant 2006;25:1241– 6. Copyright © 2006 by the International Society for Heart and Lung Transplantation.
Pulmonary hypertension (PH) increases risk of right ventricular failure and death after heart transplantation (HT).1–3 However, it is still uncertain whether PH has independent prognostic relevance in chronic heart failure (CHF). Although most analyses indicated that PH did have an independent prognostic role,4 – 6 others (including one landmark study7) did not.8 Furthermore, although serial assessment of clinical/instrumental pa-
From the aCardiology Institute, University of Bologna, Bologna; b Cardiology Institute, University of Modena, Modena; and cCardiology Institute, University of Ferrara, Ferrara, Italy. Submitted April 25, 2006; revised June 15, 2006; accepted June 27, 2006. Supported by grants from the University of Bologna, the Foundation Melloni and Banca del Monte. Reprints requests: Francesco Grigioni, MD, Istituto di Malattie dell’Apparato Cardiovascolare, Ospedale S. Orsola Malpighi, Via Massarenti 9, Bologna 40138, Italy. Telephone: XX-39-051-6364526. Fax: XX-39-051-344859. E-mail: [email protected] Copyright © 2006 by the International Society for Heart and Lung Transplantation. 1053-2498/06/$–see front matter. doi:10.1016/ j.healun.2006.06.015
rameters seems to provide additional prognostic information as compared with a single evaluation,9,10 the prognostic relevance of serial pulmonary artery pressure (PAP) measurements remains to be fully clarified. Independent prognostic significance of PH would suggest the need for a particularly strict follow-up of this group of patients to allow timely detection of indications for nonpharmacologic strategies, including HT.11,12 We analyzed the prognostic relevance of PH in a cohort of CHF patients receiving currently recommended medical treatment with available data on a large set of clinical/instrumental parameters. We also investigated whether serial measurements of PAP can provide additional prognostic information as compared with a single assessment. METHODS Eligibility Criteria and Setting All patients with an established diagnosis of CHF,13 who were referred from March 1996 through December 2003 for routine follow-up at our institution, were screened for this analysis. Eligibility criteria were: (1) 1241
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Figure 1. Flowchart of the study (see text for abbreviations).
availability of a concomitant clinical, laboratory, electrocardiographic (ECG), echocardiographic and rightheart catheterization (RHC) assessment performed at index evaluation14 –16; and (2) absence of any cause of pre-capillary PH (i.e., Classes 1, 3, 4 and 5 in the new clinical classification of PH).17 To analyze the prognostic implications of serial measurements of PAP, we searched the records of every eligible patient for a previous RHC (pre-study RHC) performed at least 6 months before the index evaluation. Our institutional protocol recommends routine RHC evaluations at least every 6 months to assess patients’ clinical condition and potential indications for HT. Such evaluations need to be performed in stable clinical conditions, with optimized medical treatment and intravascular volume.18 A flowchart of the study is shown in Figure 1. All patients provided written consent to confidential use of their data. The study was conducted in accordance with our institutional guidelines, national legal requirements and the Helsinki Declaration. Data Analysis and Definitions Continuous variables are expressed as mean ⫾ SD (or as otherwise reported), and categoric variables as numbers (percentages). Group comparisons were performed with the t-test or chi-square test, as appropriate. Follow-up of patients started at the time of index evaluation and was closed on August 1, 2004. Outcome was evaluated in terms of the combined end-point of cardiovascular death (CD) or acute heart failure (AHF), the two major adverse events in CHF. In line with the most recent guidelines,19 AHF was inferred in the presence of rapid onset of signs/symptoms indicating acute CHF decompensation requiring hospital admission or unplanned consultation at the day-hospital service of our institution’s heart failure clinic. Event rates were estimated using the Kaplan–Meier method. Follow-up of patients who underwent HT outside Status 1 (n ⫽ 68) was censored at the time of the intervention. Status 1 heart transplantation (n ⫽ 4) was considered as an event (and coded as AHF). Risk ratios (RRs) were calculated by performing Cox proportional hazards analysis on candidate variables. Clinical and laboratory index evaluation variables considered at univariate analysis were age; gender; ischemic etiology of CHF; systemic blood pressure; New York Heart Association (NYHA) class; risk factors for
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coronary artery disease; and blood values of sodium, creatinine and lipids. ECG variables analyzed were heart rate and rhythm as well as and PQ, QRS and QT durations. Echocardiographic variables were left atrial and ventricular diameters, left ventricular ejection fraction (LVEF) and presence and severity of valve lesions. RHC parameters included in the analysis were right atrial pressure, pulmonary capillary wedge pressure, mean pulmonary artery pressure (mPAP) and cardiac index. A multivariate model was constructed, testing all parameters that reached p ⬍ 0.1 at univariate analysis. To assess the prognostic significance of a single assessment of PAP, presence of PH at index evaluation (defined as mPAP ⬎25 mm Hg at rest)17 was tested as a categoric variable in the multivariate model containing all index-evaluation predictors of outcome. Mean PAP measured at index evaluation was also tested as a continuous variable. To assess the prognostic relevance of serial assessments of PAP, we first calculated the percentage of change in mPAP from pre-study to index evaluation (⌬mPAP%). To test whether serial assessments of PAP can provide incremental prognostic information as compared with a single measurement, the presence of worsening of mPAP at ⱖ75th percentile, was factored into the multivariate model as a categoric variable. In addition, ⌬mPAP% was tested as a continuous variable. All tests were performed using STATVIEW v5.0.1 software (SAS Institute, Inc., Cary, NC) for Windows. p ⬍ 0.05 was considered statistically significant. RESULTS Patients A total of 196 patients were eligible for analysis. Complete follow-up data were available for all but 2 (99%) patients. Clinical/instrumental characteristics of the study population at index evaluation are shown in Table 1. The evident impairment in clinical/instrumental parameters confirms that CHF was generally severe. The relatively young mean age likely reflects the institutional availability of a heart transplantation program. The high percentages of patients taking beta-blockers, angiotensinconverting enzyme (ACE) inhibitors and aldosterone antagonists indicates that the population was receiving optimized medical treatment.13 During a mean follow-up of 24 ⫾ 20 months, 39 (20%) patients died from cardiovascular death (CD) and 52 (27%) had at least one episode of AHF. At 3 years, the estimated survival free from the combined end-point of AHF or CD (AHF/CD) was 59 ⫾ 4% in the overall population. Prognostic Relevance of a Single Measurement of PAP An analysis of clinical/instrumental predictors of AHF/CD at index evaluation is given in Table 1. Presence of PH at index evaluation (defined as mPAP ⬎25 mm Hg at
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Table 1. Baseline Characteristics of Chronic Heart Failure Patients and Analysis of Predictors of AHF/CD Association to time to AHF/CD
Age (y) Female gender NYHA Class III or IV Systolic BP (mm Hg) Ischemic etiology Creatinine (mg/dl) Heart rate (bpm) Atrial fibrillation QRS duration (ms) LVEDD (mm) LVEF (%) Severe MR RAP (mm Hg) mPAP (mm Hg) PCP (mm Hg) CI (liters/min/m2) Beta-blockers Angiotensin-converting enzyme inhibitors Aldosterone antagonist
54 ⫾ 9 52 (27%) 96 (50%) 115 ⫾ 17 65 (33%) 1.17 ⫾ 0.6 74 ⫾ 14 31 (16%) 147 ⫾ 43 72 ⫾ 11 27 ⫾ 9 80 (40%) 6⫾4 24 ⫾ 11 16 ⫾ 9 2.6 ⫾ 0.7 169 (86%) 195 (99%) 128 (65%)
Univariate (p-value) 0.053 0.003 ⬍0.001 0.002 0.400 0.373 0.005 0.677 0.262 0.013 0.038 0.023 ⬍0.001 ⬍0.001 ⬍0.001 0.014 — — —
Multivariate (p-value) — ⬍0.001 ⬍0.001 — —
Adjusted RR (95% confidence interval) — 0.29 (0.15–0.56) 3.20 (1.95–5.26) — —
— — — — — 0.097 — ⬍0.001 — — — — —
— — — — — 1.51 (0.94–2.45) — 1.04 (1.02–1.06) — — — — —
BP, blood pressure; CI, cardiac index; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; MR, mitral regurgitation; mPAP, mean pulmonary artery pressure; PCP, mean pulmonary capillary wedge pressure; RAP, mean right atrial pressure. a RRs are expressed per unit of each determinant.
rest)17 also turned out to be an independent predictor (p ⬍ 0.001) of AHF/CD, with an adjusted risk ratio (RR) of 2.30 and 95% confidence interval (95% CI) of 1.42 to 3.73. Figure 2A depicts estimated AHF/CD-free survival at 3 years in patients with/without PH at index evaluation. Of note, mPAP values at index evaluation also retained independent prognostic significance (Table 1). Prognostic Relevance of Serial Measurements of PAP A pre-study (ⱖ6 months) RHC was available for 174 of the 196 (89%) patients (Figure 1). Patients who did and who did not have a previous RHC did not have a significant difference in age ( p ⫽ 0.72), gender ( p ⫽ 0.80), LVEF (p ⫽ 0.47), prevalence of coronary artery disease (p ⫽ 0.99) or PH (p ⫽ 0.82). Furthermore, the two groups did not appear to differ with regard to administration of ACE inhibitors, beta-blockers or aldosterone antagonists (all p ⱖ 0.13). The changes that occurred in resting hemodynamic profile from prestudy to index-evaluation RHC (during a mean of 21 ⫾ 14 months) are reported in Table 2 (none statistically significant). When a worsening in mPAP of ⱖ30% (pre-specified cut-off corresponding to the 75th percentile of ⌬mPAP%) was tested as a categoric variable in the multivariate model, including all of the index-evaluation predictors of AHF/CD (including index evaluation mPAP), this parameter turned out to be clinically predictive (adjusted RR ⫽ 2.60; 95% CI 1.45 to 4.67; p ⫽ 0.001).
Notably, worsening of mPAP by ⱖ30% retained incremental prognostic relevance even after adjusting for time-related changes recorded in the other hemodynamic parameters, including change in mean right atrial pressure (⌬mean RAP%; adjusted RR ⫽ 2.78; p ⫽ 0.003), change in mean pulmonary capillary wedge pressure (⌬mean PCP%; adjusted RR ⫽ 2.21; p ⫽ 0.033) and ⌬mean CI (adjusted RR ⫽ 2.67; p ⫽ 0.001); these findings indicate that the negative prognostic implications of time-related changes in PAP seem to be independent of changes in other hemodynamic parameters. Figure 2B depicts estimated AHF/CD-free survival at 3 years in patients with/without worsening of PAP of ⱖ30%. When percentage of change in mPAP from pre-study to index evaluation (⌬mean PAP%) was tested in the multivariate model, which included all of the index-evaluation predictors of AHF/CD (including mPAP), it turned out to be statistically significant, albeit of limited clinical relevance (RR per % ⫽ 1.005; p ⬍ 0.011) (Table 3). DISCUSSION Prevalence of CHF is increasing in the general population and reliable risk stratification is imperative to implement the most appropriate therapeutic strategies.20 A novel finding of the present study is that serial assessments of PAP can provide incremental prognostic information as compared with a single measurement recorded at a given time-point. In addition, our analysis
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Table 3. Multivariate Predictors of AHF/CD Factoring in the Percentage of Change in Mean PAP (⌬mPAP%) NYHA Class III or IV Female gender Severe mitral regurgitation mPAP (mm Hg) ⌬mPAP%
RR 95% confidence interval p 2.92 1.71–5.00 ⬍0.001 0.24 0.12–0.52 ⬍0.001 1.49 0.89–2.52 0.133 1.030a 1.004–1.057a 0.023 1.005a 1.001–1.010a 0.011
NYHA, New York Heart Association; mPAP, mean pulmonary artery pressure. a Expressed per unit of each determinant.
Figure 2. (A) Freedom from AHF/CD according to presence of PH at the time of index evaluation. (B) Freedom from AHF/CD according to presence of ⱖ30% worsening in mean pulmonary artery pressure (PAP) from pre-study to index evaluation.
provides further important evidence that a single assessment of PAP is itself a clinically useful predictor of outcome in CHF. With regard to single measurements of PAP, we found that presence of PH (i.e., mPAP ⬎25 mm Hg at rest), as defined by the most recent guidelines of the European Society of Cardiology,17 was associated with an approximately 2-fold increase in risk of adverse cardiac events, even after adjusting for a large series of clinical, ECG, laboratory and echocardiographic parameters. Of note, many of the prognostically relevant echocardiographic21,22 and/or ECG variables7,18 analyzed in the present study were not always included in previous investigations focusing on PH.4,7,8,23,24 Such
methodologic differences may partially explain previously reported discrepancies. Previous studies25 showed that functional mitral regurgitation (MR) is an independent predictor of PH in patients with left ventricular systolic dysfunction, raising the question to what extent the adverse outcome associated with PH is actually determined by the presence and severity of MR.21,22,26,27 In the present study, the negative prognostic value of PH was retained even after adjusting for the presence of severe MR. On physiologic grounds, this finding suggests that, although functional MR contributes to PH, once established, PH itself exerts an independent effect on outcome. Possible mechanisms whereby PH could negatively affect the prognosis of CHF patients include progression of right ventricular dysfunction due to increased afterload,5,28 and a negative effect of PH on neurohumoral activation.29 The present study also suggests that changes in PAP may provide relevant prognostic information. We found that time-related changes in mPAP provide independent prognostic information as compared with all the static predictors of adverse cardiac events, even after adjusting for mPAP values at presentation (Table 3). The clinical impact of changes in PAP appeared evident (again with an approximately 2-fold increase in risk) when the pre-specified cut-off was applied (a worsening of mPAP of ⱖ30%, corresponding to the 75th percentile in our cohort). Although previous studies showed that hemodynamic response to therapy may predict survival,23 this finding provides (to our knowl-
Table 2. Time-related Changes in the Principal Parameters of Resting Hemodynamic Profile According to Right-heart Catheterization (RHC)
RAP (mm Hg) mPAP (mm Hg) PCP (mm Hg) CI (liters/min/m2)
Pre-study RHC 6⫾4 25 ⫾ 12 17 ⫾ 9 2.6 ⫾ 0.8
Index evaluation RHC 6⫾4 24 ⫾ 11 16 ⫾ 9 2.6 ⫾ 0.7
Median ⌬% (25th to 75th percentile) 0 (⫺44 to 66) ⫺3 (⫺20 to 30) 0 (⫺30 to 40) 0 (⫺17 to 20)
p-value 0.707 0.604 0.634 0.796
Mean interval between pre-study and index RHC evaluation was 21 ⫾ 14 months. ⌬% represents the percentage change from pre-study to index evaluation. p-values refer to comparisons between pre-study and index evaluations. CI, cardiac index; mPAP, mean pulmonary artery pressure; PCP, mean pulmonary capillary wedge pressure; RAP, mean right atrial pressure.
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edge) the first evidence of independent clinical relevance of serial assessments of PAP in patients with optimized medical treatment, as shown by the hemodynamic profile (Table 2). It should be emphasized that the significance of time-related changes in PAP was independent of changes in other hemodynamic parameters. This observation suggests that the time-related changes in PAP do not merely provide a marker of worsening in the overall hemodynamic profile, but rather they may reflect the development of fixed obstructive changes in the small pulmonary arteries (i.e., reactive fixed PH).30 Clinical Implications Our results reinforce the concept that assessment of PH can provide an important contribution to identify highrisk groups of CHF patients.4 – 6 The finding that timerelated changes in PAP seem to provide incremental prognostic information is also of potential relevance, suggesting that patients presenting a worsening of mPAP of ⱖ30% are at high risk and should undego particularly strict follow-up to allow timely indication for transplant. Notably, in PH associated with left heart disease, the interventions with a prevalent effect on the pulmonary circulation did not produce favorable results.30,31 Strengths and Limitations of the Study This retrospective analysis (of prospectively collected data) has systematically considered a comprehensive set of relevant clinical/instrumental parameters. Further studies on the prognostic relevance of a single evaluation of PAP are warranted, if possible including noninvasive measurement5,32 of PAP and brain natriuretic peptide (BNP)8 plasma levels. Independent studies are needed to confirm the incremental prognostic relevance of serial measurement of PAP. With regard to the external validity of the present analysis, it is worth highlighting that our patients were under treatment with optimized medical therapy (Table 1). Indeed, it is uncertain to what extent previous data derived from patient populations not taking advantage of beta-blockers4,7,23,24 or aldosterone-receptor blockers4,7,23,24 can apply to current clinical practice.33,34 In the present study, AHF and CD were considered as a combined end-point: this outcome measure is highly relevant from both clinical and economic/social standpoints. Furthermore, PH retained its independent prognostic significance when CD and AHF were considered as separate end-points ( p ⱕ 0.003); the same applied for worsening PH (mPAP ⱖ30%; p ⱕ 0.012; data not shown). In the present series, data regarding cardiopulmonary exercise testing (an essential tool for prognostic stratification of CHF patients) were available for 175 patients: the independent prognostic significance of PH
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and of worsening of mPAP of ⱖ30% was retained after adjusting for the value of peak oxygen consumption (p ⱕ 0.001). In conclusion, the present cohort of 196 patients with severe CHF receiving optimized medical treatment shows that PH is of independent prognostic relevance, even after adjusting for a large set of clinical/laboratory/ instrumental parameters. Furthermore, serial measurements of PAP seem to provide additional prognostic information as compared with a single assessment. These findings suggest that serial evaluations of PAP may help identify a sub-set of high-risk CHF patients deserving a particularly close follow-up to facilitate timely detection of indications for non-pharmacologic strategies, including (when appropriate) heart transplantation. The authors are grateful to Robin M. T. Cooke for writing assistance.
REFERENCES 1. Stobierska-Dzierzek B, Awad H, Michler RE. The evolving management of acute right-sided heart failure in cardiac transplant recipients. JAMA 2001;38:923–31. 2. Cimato TR, Jessup M. Recipient selection in cardiac transplantation: contraindications and risk factors for mortality. J Heart Lung Transplant 2002;21:1161–73. 3. Trulock EP, Edwards LB, Taylor DO, Boucek MM, Keck BM, Hertz MI. The registry of the International Society for Heart and Lung Transplantation: twenty-first official adult heart transplant report—2004. J Heart Lung Transplant 2004;23:804 –15. 4. Komajda M, Jais JP, Reeves F, et al. Factors predicting mortality in idiopathic dilated cardiomyopathy. Eur Heart J 1990;11:824 –31. 5. Abramson SV, Burke JF, Kelly JJ Jr, et al. Pulmonary hypertension predicts mortality and morbidity in patients with dilated cardiomyopathy. Ann Intern Med 1992;116:888 –95. 6. Ghio S, Gavazzi A, Campana C, et al. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. JAMA 2001;37:183– 8. 7. Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95:2660 –7. 8. Gardner RS, Henderson G, McDonagh TA. The prognostic use of right heart catheterization data in patients with advanced heart failure: how relevant are invasive procedures in the risk stratification of advanced heart failure in the era of neurohormones? J Heart Lung Transplant 2005;24:303–9. 9. Grigioni F, Barbieri A, Magnani G, et al. Serial versus isolated assessment of clinical and instrumental parameters in heart failure: prognostic and therapeutic implications. Am Heart J 2003;146:298 –303. 10. Ventura HO, Mehra MR. Hippocrates and prognosis in heart failure: the challenge of static and dynamic measurements. Am Heart J 2003;146:215–7. 11. Healey JS, Davies RA, Tang AS. Improvement of apparently fixed pulmonary hypertension with cardiac resynchronization therapy. J Heart Lung Transplant 2004;23:650 –2. 12. Martin J, Siegenthaler MP, Friesewinkel O, et al. Implantable left ventricular assist device for treatment of pulmonary hypertension
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in candidates for orthotopic heart transplantation—a preliminary study. Eur J Cardiothorac Surg 2004;25:971–7. Swedberg K, Cleland J, Dargie H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 2005;26:1115– 40. Tajik A, Seward J, Hagler D, Mair D, Lie J. Two-dimensional real-time ultrasonic imaging of the heart and great vessels, technique, image orientation, structure identification, and validation. Mayo Clin Proc 1978;53:271–303. Mueller HS, Chatterjee K, Davis KB, et al. ACC expert consensus document. Present use of bedside right heart catheterization in patients with cardiac disease. American College of Cardiology. JAMA 1998;32:840 – 64. Zoghbi WA, Enriquez-Sarano M, Foster E, et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777– 802. Galie N, Torbicki A, Barst R, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension: the Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 2004;25:2243–78. Grigioni F, Carinci V, Boriani G, et al. Accelerated QRS widening as an independent predictor of cardiac death or of the need for heart transplantation in patients with congestive heart failure. J Heart Lung Transplant 2002;21:899 –902. Nieminen MS, Bohm M, Cowie MR, et al. Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the Task Force on Acute Heart Failure of the European Society of Cardiology. Eur Heart J 2005;26:384 – 416. Grigioni F, Carinci V, Favero L, et al. Hospitalization for congestive heart failure: is it still a cardiology business? Eur J Heart Fail 2002;4:99 –104. Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik AJ. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation 2001;103:1759 – 64. Grigioni F, Detaint D, Avierinos JF, Scott C, Tajik J, EnriquezSarano M. Contribution of ischemic mitral regurgitation to congestive heart failure after myocardial infarction. JAMA 2005;45: 260 –7.
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23. Stevenson LW, Tillisch JH, Hamilton M, et al. Importance of hemodynamic response to therapy in predicting survival with ejection fraction less than or equal to 20% secondary to ischemic or nonischemic dilated cardiomyopathy. Am J Cardiol 1990;66: 1348 –54. 24. Saxon LA, Stevenson WG, Middlekauff HR, et al. Predicting death from progressive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1993;72:62–5. 25. Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary hypertension in left ventricular dysfunction. JAMA 1997;29:153–9. 26. Blondheim D, Jacobs L, Kotler M. Dilated cardiomyopathy with mitral regurgitation: decreased survival despite a low frequency of left ventricular thrombus. Am Heart J 1991;122:763–71. 27. Bursi F, Enriquez-Sarano M, Nkomo VT, et al. Heart failure and death after myocardial infarction in the community: the emerging role of mitral regurgitation. Circulation 2005;111:295–301. 28. Cowburn PJ, Cleland JG, Coats AJ, Komajda M. Risk stratification in chronic heart failure. Eur Heart J 1998;19:696 –710. 29. Cody R, Haas G, Binkley P, Capers Q, Kelley R. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation 1992;85:504 –9. 30. Galie N, Simonneau G. Pulmonary hypertension. The ESC textbook of cardiovascular medicine. Oxford:Blackwell Publishing, 2006. 31. Chua R, Keogh A, Miyashita M. Novel use of sildenafil in the treatment of portopulmonary hypertension. J Heart Lung Transplant 2005;24:498 –500. 32. Lanzarini L, Fontana A, Campana C, Klersy C. Two simple echo-Doppler measurements can accurately identify pulmonary hypertension in the large majority of patients with chronic heart failure. J Heart Lung Transplant 2005;24:745–54. 33. Hunt S, Baker D, Chin M, et al. ACC/AHA guidelines for the evaluation and managment of chronic heart failure in the adult: executive summary: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. JAMA 2001;38:2101–13. 34. Remme WJ, Swedberg K. Comprehensive guidelines for the diagnosis and treatment of chronic heart failure. Task force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Eur J Heart Fail 2002;4:11–22.
Pulmonary hypertension (PH) increases risk of right ventricular failure and death after heart transplantation (HT).1–3 However, it is still uncertain whether PH has independent prognostic relevance in chronic heart failure (CHF). Although most analyses indicated that PH did have an independent prognostic role,4 – 6 others (including one landmark study7) did not.8 Furthermore, although serial assessment of clinical/instrumental pa-
From the aCardiology Institute, University of Bologna, Bologna; b Cardiology Institute, University of Modena, Modena; and cCardiology Institute, University of Ferrara, Ferrara, Italy. Submitted April 25, 2006; revised June 15, 2006; accepted June 27, 2006. Supported by grants from the University of Bologna, the Foundation Melloni and Banca del Monte. Reprints requests: Francesco Grigioni, MD, Istituto di Malattie dell’Apparato Cardiovascolare, Ospedale S. Orsola Malpighi, Via Massarenti 9, Bologna 40138, Italy. Telephone: XX-39-051-6364526. Fax: XX-39-051-344859. E-mail: [email protected] Copyright © 2006 by the International Society for Heart and Lung Transplantation. 1053-2498/06/$–see front matter. doi:10.1016/ j.healun.2006.06.015
rameters seems to provide additional prognostic information as compared with a single evaluation,9,10 the prognostic relevance of serial pulmonary artery pressure (PAP) measurements remains to be fully clarified. Independent prognostic significance of PH would suggest the need for a particularly strict follow-up of this group of patients to allow timely detection of indications for nonpharmacologic strategies, including HT.11,12 We analyzed the prognostic relevance of PH in a cohort of CHF patients receiving currently recommended medical treatment with available data on a large set of clinical/instrumental parameters. We also investigated whether serial measurements of PAP can provide additional prognostic information as compared with a single assessment. METHODS Eligibility Criteria and Setting All patients with an established diagnosis of CHF,13 who were referred from March 1996 through December 2003 for routine follow-up at our institution, were screened for this analysis. Eligibility criteria were: (1) 1241
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Figure 1. Flowchart of the study (see text for abbreviations).
availability of a concomitant clinical, laboratory, electrocardiographic (ECG), echocardiographic and rightheart catheterization (RHC) assessment performed at index evaluation14 –16; and (2) absence of any cause of pre-capillary PH (i.e., Classes 1, 3, 4 and 5 in the new clinical classification of PH).17 To analyze the prognostic implications of serial measurements of PAP, we searched the records of every eligible patient for a previous RHC (pre-study RHC) performed at least 6 months before the index evaluation. Our institutional protocol recommends routine RHC evaluations at least every 6 months to assess patients’ clinical condition and potential indications for HT. Such evaluations need to be performed in stable clinical conditions, with optimized medical treatment and intravascular volume.18 A flowchart of the study is shown in Figure 1. All patients provided written consent to confidential use of their data. The study was conducted in accordance with our institutional guidelines, national legal requirements and the Helsinki Declaration. Data Analysis and Definitions Continuous variables are expressed as mean ⫾ SD (or as otherwise reported), and categoric variables as numbers (percentages). Group comparisons were performed with the t-test or chi-square test, as appropriate. Follow-up of patients started at the time of index evaluation and was closed on August 1, 2004. Outcome was evaluated in terms of the combined end-point of cardiovascular death (CD) or acute heart failure (AHF), the two major adverse events in CHF. In line with the most recent guidelines,19 AHF was inferred in the presence of rapid onset of signs/symptoms indicating acute CHF decompensation requiring hospital admission or unplanned consultation at the day-hospital service of our institution’s heart failure clinic. Event rates were estimated using the Kaplan–Meier method. Follow-up of patients who underwent HT outside Status 1 (n ⫽ 68) was censored at the time of the intervention. Status 1 heart transplantation (n ⫽ 4) was considered as an event (and coded as AHF). Risk ratios (RRs) were calculated by performing Cox proportional hazards analysis on candidate variables. Clinical and laboratory index evaluation variables considered at univariate analysis were age; gender; ischemic etiology of CHF; systemic blood pressure; New York Heart Association (NYHA) class; risk factors for
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coronary artery disease; and blood values of sodium, creatinine and lipids. ECG variables analyzed were heart rate and rhythm as well as and PQ, QRS and QT durations. Echocardiographic variables were left atrial and ventricular diameters, left ventricular ejection fraction (LVEF) and presence and severity of valve lesions. RHC parameters included in the analysis were right atrial pressure, pulmonary capillary wedge pressure, mean pulmonary artery pressure (mPAP) and cardiac index. A multivariate model was constructed, testing all parameters that reached p ⬍ 0.1 at univariate analysis. To assess the prognostic significance of a single assessment of PAP, presence of PH at index evaluation (defined as mPAP ⬎25 mm Hg at rest)17 was tested as a categoric variable in the multivariate model containing all index-evaluation predictors of outcome. Mean PAP measured at index evaluation was also tested as a continuous variable. To assess the prognostic relevance of serial assessments of PAP, we first calculated the percentage of change in mPAP from pre-study to index evaluation (⌬mPAP%). To test whether serial assessments of PAP can provide incremental prognostic information as compared with a single measurement, the presence of worsening of mPAP at ⱖ75th percentile, was factored into the multivariate model as a categoric variable. In addition, ⌬mPAP% was tested as a continuous variable. All tests were performed using STATVIEW v5.0.1 software (SAS Institute, Inc., Cary, NC) for Windows. p ⬍ 0.05 was considered statistically significant. RESULTS Patients A total of 196 patients were eligible for analysis. Complete follow-up data were available for all but 2 (99%) patients. Clinical/instrumental characteristics of the study population at index evaluation are shown in Table 1. The evident impairment in clinical/instrumental parameters confirms that CHF was generally severe. The relatively young mean age likely reflects the institutional availability of a heart transplantation program. The high percentages of patients taking beta-blockers, angiotensinconverting enzyme (ACE) inhibitors and aldosterone antagonists indicates that the population was receiving optimized medical treatment.13 During a mean follow-up of 24 ⫾ 20 months, 39 (20%) patients died from cardiovascular death (CD) and 52 (27%) had at least one episode of AHF. At 3 years, the estimated survival free from the combined end-point of AHF or CD (AHF/CD) was 59 ⫾ 4% in the overall population. Prognostic Relevance of a Single Measurement of PAP An analysis of clinical/instrumental predictors of AHF/CD at index evaluation is given in Table 1. Presence of PH at index evaluation (defined as mPAP ⬎25 mm Hg at
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Table 1. Baseline Characteristics of Chronic Heart Failure Patients and Analysis of Predictors of AHF/CD Association to time to AHF/CD
Age (y) Female gender NYHA Class III or IV Systolic BP (mm Hg) Ischemic etiology Creatinine (mg/dl) Heart rate (bpm) Atrial fibrillation QRS duration (ms) LVEDD (mm) LVEF (%) Severe MR RAP (mm Hg) mPAP (mm Hg) PCP (mm Hg) CI (liters/min/m2) Beta-blockers Angiotensin-converting enzyme inhibitors Aldosterone antagonist
54 ⫾ 9 52 (27%) 96 (50%) 115 ⫾ 17 65 (33%) 1.17 ⫾ 0.6 74 ⫾ 14 31 (16%) 147 ⫾ 43 72 ⫾ 11 27 ⫾ 9 80 (40%) 6⫾4 24 ⫾ 11 16 ⫾ 9 2.6 ⫾ 0.7 169 (86%) 195 (99%) 128 (65%)
Univariate (p-value) 0.053 0.003 ⬍0.001 0.002 0.400 0.373 0.005 0.677 0.262 0.013 0.038 0.023 ⬍0.001 ⬍0.001 ⬍0.001 0.014 — — —
Multivariate (p-value) — ⬍0.001 ⬍0.001 — —
Adjusted RR (95% confidence interval) — 0.29 (0.15–0.56) 3.20 (1.95–5.26) — —
— — — — — 0.097 — ⬍0.001 — — — — —
— — — — — 1.51 (0.94–2.45) — 1.04 (1.02–1.06) — — — — —
BP, blood pressure; CI, cardiac index; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; MR, mitral regurgitation; mPAP, mean pulmonary artery pressure; PCP, mean pulmonary capillary wedge pressure; RAP, mean right atrial pressure. a RRs are expressed per unit of each determinant.
rest)17 also turned out to be an independent predictor (p ⬍ 0.001) of AHF/CD, with an adjusted risk ratio (RR) of 2.30 and 95% confidence interval (95% CI) of 1.42 to 3.73. Figure 2A depicts estimated AHF/CD-free survival at 3 years in patients with/without PH at index evaluation. Of note, mPAP values at index evaluation also retained independent prognostic significance (Table 1). Prognostic Relevance of Serial Measurements of PAP A pre-study (ⱖ6 months) RHC was available for 174 of the 196 (89%) patients (Figure 1). Patients who did and who did not have a previous RHC did not have a significant difference in age ( p ⫽ 0.72), gender ( p ⫽ 0.80), LVEF (p ⫽ 0.47), prevalence of coronary artery disease (p ⫽ 0.99) or PH (p ⫽ 0.82). Furthermore, the two groups did not appear to differ with regard to administration of ACE inhibitors, beta-blockers or aldosterone antagonists (all p ⱖ 0.13). The changes that occurred in resting hemodynamic profile from prestudy to index-evaluation RHC (during a mean of 21 ⫾ 14 months) are reported in Table 2 (none statistically significant). When a worsening in mPAP of ⱖ30% (pre-specified cut-off corresponding to the 75th percentile of ⌬mPAP%) was tested as a categoric variable in the multivariate model, including all of the index-evaluation predictors of AHF/CD (including index evaluation mPAP), this parameter turned out to be clinically predictive (adjusted RR ⫽ 2.60; 95% CI 1.45 to 4.67; p ⫽ 0.001).
Notably, worsening of mPAP by ⱖ30% retained incremental prognostic relevance even after adjusting for time-related changes recorded in the other hemodynamic parameters, including change in mean right atrial pressure (⌬mean RAP%; adjusted RR ⫽ 2.78; p ⫽ 0.003), change in mean pulmonary capillary wedge pressure (⌬mean PCP%; adjusted RR ⫽ 2.21; p ⫽ 0.033) and ⌬mean CI (adjusted RR ⫽ 2.67; p ⫽ 0.001); these findings indicate that the negative prognostic implications of time-related changes in PAP seem to be independent of changes in other hemodynamic parameters. Figure 2B depicts estimated AHF/CD-free survival at 3 years in patients with/without worsening of PAP of ⱖ30%. When percentage of change in mPAP from pre-study to index evaluation (⌬mean PAP%) was tested in the multivariate model, which included all of the index-evaluation predictors of AHF/CD (including mPAP), it turned out to be statistically significant, albeit of limited clinical relevance (RR per % ⫽ 1.005; p ⬍ 0.011) (Table 3). DISCUSSION Prevalence of CHF is increasing in the general population and reliable risk stratification is imperative to implement the most appropriate therapeutic strategies.20 A novel finding of the present study is that serial assessments of PAP can provide incremental prognostic information as compared with a single measurement recorded at a given time-point. In addition, our analysis
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Table 3. Multivariate Predictors of AHF/CD Factoring in the Percentage of Change in Mean PAP (⌬mPAP%) NYHA Class III or IV Female gender Severe mitral regurgitation mPAP (mm Hg) ⌬mPAP%
RR 95% confidence interval p 2.92 1.71–5.00 ⬍0.001 0.24 0.12–0.52 ⬍0.001 1.49 0.89–2.52 0.133 1.030a 1.004–1.057a 0.023 1.005a 1.001–1.010a 0.011
NYHA, New York Heart Association; mPAP, mean pulmonary artery pressure. a Expressed per unit of each determinant.
Figure 2. (A) Freedom from AHF/CD according to presence of PH at the time of index evaluation. (B) Freedom from AHF/CD according to presence of ⱖ30% worsening in mean pulmonary artery pressure (PAP) from pre-study to index evaluation.
provides further important evidence that a single assessment of PAP is itself a clinically useful predictor of outcome in CHF. With regard to single measurements of PAP, we found that presence of PH (i.e., mPAP ⬎25 mm Hg at rest), as defined by the most recent guidelines of the European Society of Cardiology,17 was associated with an approximately 2-fold increase in risk of adverse cardiac events, even after adjusting for a large series of clinical, ECG, laboratory and echocardiographic parameters. Of note, many of the prognostically relevant echocardiographic21,22 and/or ECG variables7,18 analyzed in the present study were not always included in previous investigations focusing on PH.4,7,8,23,24 Such
methodologic differences may partially explain previously reported discrepancies. Previous studies25 showed that functional mitral regurgitation (MR) is an independent predictor of PH in patients with left ventricular systolic dysfunction, raising the question to what extent the adverse outcome associated with PH is actually determined by the presence and severity of MR.21,22,26,27 In the present study, the negative prognostic value of PH was retained even after adjusting for the presence of severe MR. On physiologic grounds, this finding suggests that, although functional MR contributes to PH, once established, PH itself exerts an independent effect on outcome. Possible mechanisms whereby PH could negatively affect the prognosis of CHF patients include progression of right ventricular dysfunction due to increased afterload,5,28 and a negative effect of PH on neurohumoral activation.29 The present study also suggests that changes in PAP may provide relevant prognostic information. We found that time-related changes in mPAP provide independent prognostic information as compared with all the static predictors of adverse cardiac events, even after adjusting for mPAP values at presentation (Table 3). The clinical impact of changes in PAP appeared evident (again with an approximately 2-fold increase in risk) when the pre-specified cut-off was applied (a worsening of mPAP of ⱖ30%, corresponding to the 75th percentile in our cohort). Although previous studies showed that hemodynamic response to therapy may predict survival,23 this finding provides (to our knowl-
Table 2. Time-related Changes in the Principal Parameters of Resting Hemodynamic Profile According to Right-heart Catheterization (RHC)
RAP (mm Hg) mPAP (mm Hg) PCP (mm Hg) CI (liters/min/m2)
Pre-study RHC 6⫾4 25 ⫾ 12 17 ⫾ 9 2.6 ⫾ 0.8
Index evaluation RHC 6⫾4 24 ⫾ 11 16 ⫾ 9 2.6 ⫾ 0.7
Median ⌬% (25th to 75th percentile) 0 (⫺44 to 66) ⫺3 (⫺20 to 30) 0 (⫺30 to 40) 0 (⫺17 to 20)
p-value 0.707 0.604 0.634 0.796
Mean interval between pre-study and index RHC evaluation was 21 ⫾ 14 months. ⌬% represents the percentage change from pre-study to index evaluation. p-values refer to comparisons between pre-study and index evaluations. CI, cardiac index; mPAP, mean pulmonary artery pressure; PCP, mean pulmonary capillary wedge pressure; RAP, mean right atrial pressure.
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edge) the first evidence of independent clinical relevance of serial assessments of PAP in patients with optimized medical treatment, as shown by the hemodynamic profile (Table 2). It should be emphasized that the significance of time-related changes in PAP was independent of changes in other hemodynamic parameters. This observation suggests that the time-related changes in PAP do not merely provide a marker of worsening in the overall hemodynamic profile, but rather they may reflect the development of fixed obstructive changes in the small pulmonary arteries (i.e., reactive fixed PH).30 Clinical Implications Our results reinforce the concept that assessment of PH can provide an important contribution to identify highrisk groups of CHF patients.4 – 6 The finding that timerelated changes in PAP seem to provide incremental prognostic information is also of potential relevance, suggesting that patients presenting a worsening of mPAP of ⱖ30% are at high risk and should undego particularly strict follow-up to allow timely indication for transplant. Notably, in PH associated with left heart disease, the interventions with a prevalent effect on the pulmonary circulation did not produce favorable results.30,31 Strengths and Limitations of the Study This retrospective analysis (of prospectively collected data) has systematically considered a comprehensive set of relevant clinical/instrumental parameters. Further studies on the prognostic relevance of a single evaluation of PAP are warranted, if possible including noninvasive measurement5,32 of PAP and brain natriuretic peptide (BNP)8 plasma levels. Independent studies are needed to confirm the incremental prognostic relevance of serial measurement of PAP. With regard to the external validity of the present analysis, it is worth highlighting that our patients were under treatment with optimized medical therapy (Table 1). Indeed, it is uncertain to what extent previous data derived from patient populations not taking advantage of beta-blockers4,7,23,24 or aldosterone-receptor blockers4,7,23,24 can apply to current clinical practice.33,34 In the present study, AHF and CD were considered as a combined end-point: this outcome measure is highly relevant from both clinical and economic/social standpoints. Furthermore, PH retained its independent prognostic significance when CD and AHF were considered as separate end-points ( p ⱕ 0.003); the same applied for worsening PH (mPAP ⱖ30%; p ⱕ 0.012; data not shown). In the present series, data regarding cardiopulmonary exercise testing (an essential tool for prognostic stratification of CHF patients) were available for 175 patients: the independent prognostic significance of PH
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and of worsening of mPAP of ⱖ30% was retained after adjusting for the value of peak oxygen consumption (p ⱕ 0.001). In conclusion, the present cohort of 196 patients with severe CHF receiving optimized medical treatment shows that PH is of independent prognostic relevance, even after adjusting for a large set of clinical/laboratory/ instrumental parameters. Furthermore, serial measurements of PAP seem to provide additional prognostic information as compared with a single assessment. These findings suggest that serial evaluations of PAP may help identify a sub-set of high-risk CHF patients deserving a particularly close follow-up to facilitate timely detection of indications for non-pharmacologic strategies, including (when appropriate) heart transplantation. The authors are grateful to Robin M. T. Cooke for writing assistance.
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23. Stevenson LW, Tillisch JH, Hamilton M, et al. Importance of hemodynamic response to therapy in predicting survival with ejection fraction less than or equal to 20% secondary to ischemic or nonischemic dilated cardiomyopathy. Am J Cardiol 1990;66: 1348 –54. 24. Saxon LA, Stevenson WG, Middlekauff HR, et al. Predicting death from progressive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1993;72:62–5. 25. Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary hypertension in left ventricular dysfunction. JAMA 1997;29:153–9. 26. Blondheim D, Jacobs L, Kotler M. Dilated cardiomyopathy with mitral regurgitation: decreased survival despite a low frequency of left ventricular thrombus. Am Heart J 1991;122:763–71. 27. Bursi F, Enriquez-Sarano M, Nkomo VT, et al. Heart failure and death after myocardial infarction in the community: the emerging role of mitral regurgitation. Circulation 2005;111:295–301. 28. Cowburn PJ, Cleland JG, Coats AJ, Komajda M. Risk stratification in chronic heart failure. Eur Heart J 1998;19:696 –710. 29. Cody R, Haas G, Binkley P, Capers Q, Kelley R. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation 1992;85:504 –9. 30. Galie N, Simonneau G. Pulmonary hypertension. The ESC textbook of cardiovascular medicine. Oxford:Blackwell Publishing, 2006. 31. Chua R, Keogh A, Miyashita M. Novel use of sildenafil in the treatment of portopulmonary hypertension. J Heart Lung Transplant 2005;24:498 –500. 32. Lanzarini L, Fontana A, Campana C, Klersy C. Two simple echo-Doppler measurements can accurately identify pulmonary hypertension in the large majority of patients with chronic heart failure. J Heart Lung Transplant 2005;24:745–54. 33. Hunt S, Baker D, Chin M, et al. ACC/AHA guidelines for the evaluation and managment of chronic heart failure in the adult: executive summary: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. JAMA 2001;38:2101–13. 34. Remme WJ, Swedberg K. Comprehensive guidelines for the diagnosis and treatment of chronic heart failure. Task force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Eur J Heart Fail 2002;4:11–22.