CLINICAL STUDY: ANGIOTENSIN ANTAGONISTS AND HEART FAILURE
Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study
Maylene Wong, MD, FACC*,*,
Lidia Staszewsky, MD ,
Roberto Latini, MD,
Simona Barlera, MS,
Alberto Volpi, MD, FACC ,
Yann-Tong Chiang, PhD ,
Raymond L. Benza, MD, FACC||,
Sidney O. Gottlieb, MD, FACC¶,
Thomas D. Kleemann, MD#,
Franco Rosconi, MD**,
Pieter M. Vandervoort, MD, FACC,
Jay N. Cohn, MD, FACC Val-HeFT Heart Failure Trial Investigators
* VA Greater Los Angeles Healthcare System and University of California at Los Angeles, California, USA
Istituto Mario Negri, Milan, Italy
Istituto Mario Negri and "C Borella" Hospital, Milan, Italy
Novartis Pharmaceuticals, East Orange, New Jersey, USA
|| University of Alabama, Birmingham, Alabama, USA
¶ Mid-Atlantic Cardiovascular Associates, Baltimore, Maryland, USA
# Herzzentrum Ludwigshafen, Ludwigshafen, Germany
** Ospedale Passirana di Rho, Milan, Italy
Hartcentrum Limburg, Genk, Belgium
University of Minnesota, Minneapolis, Minnesota, USA
Manuscript received January 29, 2002;
revised manuscript received May 29, 2002,
accepted May 31, 2002.
* Reprint requests and correspondence: Dr. Maylene Wong, (00QM), VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, California 90073, USA.
maylene.wong{at}med.va.gov
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Abstract
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OBJECTIVES: The objective of the study was to evaluate the effect of an angiotensin receptor blocker on left ventricular (LV) structure and function when added to prescribed heart failure therapy.
BACKGROUND: The clinical benefit derived from heart failure therapy is attributed to the regression of LV remodeling.
METHODS: At 302 multinational sites, 5,010 patients in New York Heart Association (NYHA) classification II to IV heart failure taking angiotensin-converting enzyme inhibitor (ACEI) and/or beta-blocker (BB) were randomized into valsartan and placebo groups and followed for a mean of 22.4 months. Serial echocardiographic measurements of left ventricular internal diastolic diameter (LVIDd) and ejection fraction (EF) were recorded. Total study reproducibility calculated to 90% power at 5% significance defined detectable differences of 0.09 cm for LVIDd and 0.86% for EF.
RESULTS: Baseline LVIDd and EF for valsartan and placebo groups were similar: 3.6 ± 0.5 versus 3.7 ± 0.5 (cm/m2) and 26.6 ± 7.3 versus 26.9 ± 7.0 (%). Mean group changes from baseline over time were compared. Significant decrease in LVIDd and increase in EF began by four months, reached plateau by one year, and persisted to two years in valsartan compared with placebo patients, irrespective of age, gender, race, etiology, NYHA classification, and co-treatment therapy. Changes at 18 months were –0.12 ± 0.4 versus –0.05 ± 0.4 (cm/m2), p < 0.00001 for LVIDd, and +4.5 ± 8.9 versus +3.2 ± 8.6 (%), p < 0.00001 for EF. The exception occurred in patients taking both ACEI and BB as co-treatment, in whom the decrease in LVIDd and increase in EF were no different between valsartan and placebo groups.
CONCLUSIONS: The Val-HeFT echocardiographic substudy of 5,010 patients with moderate heart failure demonstrated that valsartan therapy taken with either ACEI or BB reversed LV remodeling.
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Abbreviations and Acronyms
| | ACEI | | angiotensin-converting enzyme inhibitor | | ANCOVA | | analysis of covariance | | ARB | | angiotensin receptor blocker | | ANGII | | angiotensin II | | BB | | beta-blocker | | EF | | ejection fraction | | LV | | left ventricular | | LVIDd | | left ventricular internal diastolic diameter | | LVIDd/BSA | | left ventricular internal diastolic diameter/body surface area | | NYHA | | New York Heart Association | | RAAS | | renin-angiotensin-aldosterone system | | Val-HeFT | | Valsartan in Heart Failure Trial |
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Recent clinical trials in patients with heart failure have demonstrated remarkable reductions in mortality and morbidity with the introduction of nitrate and hydralazine, angiotensin-converting enzyme inhibitors (ACEIs) and beta-blockers (BBs) (1–4). A common finding has been that the drugs that exert a favorable effect on outcome also result in an increase in ejection fraction (EF) or a reduction in left ventricular (LV) dimension (5–8). This favorable effect on LV chamber size and function has been attributed to regression of structural remodeling (9).
Echocardiography has been performed in some trials as a substudy in a small sample of the overall study population. Although this strategy has made it possible to identify the average effect of the agent under study, the limited sample could only imply a relationship between changes in echocardiographic measurements and outcome, and could not examine the variability of responses in subgroups of the population (10–12).
The objectives of the Valsartan in Heart Failure Trial (Val-HeFT) were to assess the effect of the addition of valsartan (Novartis Pharma AG, Basel, Switzerland), an angiotensin receptor blocker (ARB), on mortality and morbidity, and on secondary end points, including signs and symptoms, quality of life, and neurohormonal and echocardiographic variables in patients already receiving standard therapy, including ACEI and/or BB. The study showed that all-cause mortality was similar for valsartan and placebo patients (p = 0.801). However, the valsartan group showed a reduction in combined all-cause mortality and morbidity compared to placebo (p = 0.009). Valsartan patients also experienced significant improvements in the symptomatic and quality of life variables (13). The aims of the echocardiographic examination were to evaluate the effect of valsartan on left ventricular internal diastolic diameter (LVIDd) and EF as secondary variables with the entry criteria of >2.9 cm/m2 and <40% respectively. With a large recruitment and echocardiography planned for all patients, Val-HeFT provided the advantage of examining the effects of valsartan on ventricular remodeling in the whole population as well as in subgroups, including those based on background drug therapy.
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Methods
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In the Val-HeFT echocardiography study, three core laboratories (Los Angeles, Milan, and Stockholm) qualified 291 laboratories based on single and duplicate readings of seven variables: end-systolic and end-diastolic diameters, lengths, and volumes; and EF. The measurements were derived from two-dimensionally directed M-mode recordings from the parasternal short-axis view, and apical four-chamber view using the area-length method. Quality of recording was defined by a scoring system; accuracy of reading, by agreement with core readings; reproducibility, and by agreement between duplicate studies. After randomization, recording quality and reading accuracy of the study end points, LVIDd and EF, were monitored from a random sampling of studies measured at baseline, 4, 12, and 18 months into the trial. The qualifying process brought 95% of the sites to an equivalent level of quality. The monitoring process showed that recording quality and reading accuracy were maintained during the trial. From a retrospective power analysis using the sites’ reproducibility and a population of 4,000 patients to 90% power with a significance level of 5%, detectable change between treatment and placebo groups at a single point in time were calculated: the detectable difference for LVIDd was 0.09 cm and for EF, 0.86%. Details have been reported in a method paper (14).
Statistical analyses.
Measurements of LVIDd and EF were performed locally at each site and sent to the data center for analysis. LVIDd/BSA values were obtained by adjusting LVIDd by each patient’s body surface area (BSA). Analysis of covariance (ANCOVA) was performed to analyze change from baseline in LVIDd/BSA and EF at four, 12, 18, and 24 months, and at end point (last post-randomization observation carried forward). The ANCOVA model applied included effects for treatment group, pooled center, baseline value, baseline use of ACEI and/or BB, and treatment by baseline value interaction. Comparisons between valsartan and placebo were made for all patients and within exploratory subgroups categorized by age, gender, race, and concurrent use of ACEI and BB. Between-treatment comparisons were based on least-squares treatment group means from the ANCOVA, which were adjusted for differences among patients with respect to other effects in the ANCOVA model. All statistical comparisons presented are for a significance level of p < 0.05. Between-treatment comparisons of mean change from baseline in blood pressures and heart rates were made at 4, 12, 18, and 24 months, and at end point using ANCOVA.
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Results
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Baseline characteristics and demographics have already been published, and no clinically relevant differences between the valsartan and placebo groups were found (13,15). Briefly summarized, the study population was predominantly white (90%) and averaged 63 years of age, with a male/female distribution of 4/1. Ninety-eight percent of patients (62% and 36%, respectively) were in New York Heart Association (NYHA) functional class II and III, and ischemia was the etiology of heart failure in 57%. Ninety-three percent of patients were on ACEI therapy and 35% were on BB therapy. The echocardiographic baseline measurements and the distribution of the total population randomized to valsartan and placebo are summarized in Table 1. Baseline LVIDd/BSA and EF were generally equivalent for valsartan and placebo patients, whether considered as a whole or separated into age, gender, race, etiology, NYHA classification, and co-treatment subgroups. This baseline equivalence in EF was also seen between patients taking a BB alone or with an ACEI (+ACEI+BB and +BB–ACEI) and patients not taking a BB (+ACEI–BB and –BB–ACEI) (+ indicates co-treatment; – indicates not a co-treatment) . The overall mean ± SD baseline LVIDd/BSA and EF for valsartan patients were 3.6 ± 0.5 cm/m2 and 26.6 ± 7.3%, and for placebo patients, 3.7 ± 0.5 cm/m2 and 26.9 ± 7.0%, respectively.
Figure 1 illustrates the mean changes from baseline in EF and LVIDd/BSA at four, 12, 18, and 24 months, and at end point (last available observation after baseline carried forward) for the two treatment groups. A statistically significant increase in EF (p = 0.00075) and decrease in LVIDd/BSA (p = 0.00002) were observed with valsartan compared to placebo. With valsartan, EF increased and LVIDd/BSA decreased from baseline values starting at four months and persisting throughout the follow-up period for patients remaining under echocardiographic evaluation. The between-treatment differences in mean change from baseline were statistically significant at all observation periods, with valsartan providing larger increases in EF and larger decreases in LVIDd/BSA than placebo. In the placebo group the increase in EF and decrease in LVIDd progressed continuously for 24 months.
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Figure 1 Effects of valsartan on left ventricular internal diastolic diameter/body surface area (LVIDd/BSA) and ejection fraction (EF) compared to placebo: change from baseline to month of observation. The histobars represent mean changes (adjusted for effects for treatment group, pooled center, baseline value, baseline use of angiotensin-converting enzyme inhibitor or beta blocker, and treatment by baseline value interaction by analysis of covariance) between baseline values and those at months 4, 12, 18, 24, and at end point (last observation available carried forward) for valsartan (black bars) and placebo (white bars). Baseline values at each observation period are adjusted for the number of patients with available data. Change is expressed in absolute units for EF (%) and LVIDd/BSA (cm/m2). The p values for the between-treatment comparison are determined from least-squares mean change.
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Figure 2 summarizes the mean changes from baseline to end point in EF and LVIDd/BSA for valsartan and placebo patients by co-treatment subgroups, +ACEI+BB, +ACEI–BB, +BB–ACEI, and –BB–ACEI with adjustments by ANCOVA. In every group, except those patients taking both ACEI and BB, valsartan produced a rise in EF and a reduction in LVIDd/BSA of significance compared to placebo, with the exception of EF in the relatively small –BB–ACEI group (n = 102) in which the 1.3% unit greater increase in the valsartan group did not reach statistical significance. In the patients taking both co-treatments, valsartan did not produce further improvement in EF and LVIDd/BSA.
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Figure 2 Effects of valsartan on left ventricular internal diastolic diameter/body surface area (LVIDd/BSA) and ejection fraction (EF) compared to placebo by co-treatment group: change from baseline to end point. The histobars represent mean changes (adjusted for effects for treatment group, pooled center, baseline value, baseline use of angiotensin-converting enzyme inhibitor [ACEI] and/or beta-blocker [BB], and treatment-by-baseline value interaction by analysis of covariance) between baseline values and those at end point (last observation available carried forward) for co-treatment subgroups randomized to valsartan (black bars) and placebo (white bars) groups. Baseline values at each observation period are adjusted for the number of patients with available end point data. Change is expressed in absolute units for EF (%) and LVIDd/BSA (cm/m2). The p values for the valsartan versus placebo comparison are determined from least-squares mean change. Subgroups are designated by (+) = co-treatment and (–) = not a co-treatment with ACEI and BB.
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Systolic blood pressure was reduced by a greater extent with valsartan than placebo, –5.2 ± 15.8 (mean ± SD) mm Hg versus –1.2 ± 14.8 at four months (p < 0.0001), and –5.2 ± 16.0 mm Hg versus –1.3 ± 15.9 at one year (p < 0.0001). Valsartan slowed heart rate by 0.3 to 0.8 beats/min more than placebo, with statistically significant differences at month 4 (p < 0.005) and 12 (p < 0.05).
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Discussion
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The objective of the Val-HeFT echocardiographic examination was to study the effects of valsartan treatment on LVIDd and EF as secondary outcomes. The results from serial echocardiograms recorded and read locally on 5,010 patients were conclusive: diastolic dimension is reduced and systolic function is improved, both being statistically significant in the group of patients receiving valsartan in addition to their prescribed treatment compared to placebo. Because all of the patients were studied echocardiographically, the relationship between outcomes and LV structure and function was confirmed. In addition, the large volume of studies provided sufficient data to track the relationship between outcomes and LV remodeling in subgroups of patients. The most notable subgroup differences emerged in those treated with different background neurohormonal-inhibiting therapy (13).
In the subgroups treated with either ACEI or BB, or neither, valsartan demonstrated significant baseline-to-end point changes for EF and LVIDd compared to placebo. As previously reported (13), these subgroups exhibited a favorable effect of valsartan on combined morbidity-mortality, and a trend for a benefit on mortality. Valsartan produced similar benefit on remodeling and outcomes in the subgroup not taking ACEI, with or without BB, despite the small population of less than 10% of the total recruitment (Fig. 2). In distinct contrast, in the subgroup treated with both ACEI and BB, valsartan showed no effect on LV remodeling and, as previously reported, showed a trend for an adverse effect on morbidity and mortality.
Background therapy probably played a role in the unusually positive placebo effect on LVIDd and EF. The sustained two-year decrease in LV diameter and increase in LV emptying may reflect a delayed response to co-treatment, particularly to BB, which require several months to achieve maximum change in LV remodeling and function (16). Both the design of the study, which mandated stability of background treatment for only two to four weeks, and the baseline findings, which found patients taking BB and not taking BB to have equivalent EF and LVIDd, corroborate a delayed response to co-treatment in the placebo group.
The mechanism of the favorable effect of valsartan on outcome and LV remodeling must remain conjectural; however, the results suggest that angiotensin II (ANGII) contributes to the progression of heart failure even in patients treated with ACEI and BB, both of which act to inhibit the renin-angiotensin-aldosterone system (RAAS). Because ANGII is formed by angiotensin-converting enzyme and non–angiotensin-converting enzyme pathways, distal blockade with an ARB provides more complete blockade of the RAAS (17). Although ANGII acts at multiple sites, a plausible mechanism of valsartan action is on ANGII that directly affects the structural abnormalities in the left ventricle by its known mitogenic effect (18–20). As valsartan also lowered systolic blood pressure by an average of 5 mm Hg, afterload reduction cannot be excluded as a factor in the anti-remodeling result. The experience with vasodilators is mixed, with prazosin producing a sustained blood pressure fall without improving EF (21), and felodipine lowering blood pressure and increasing EF from the same LVIDd (22). Nevertheless, ANGII is ubiquitous and any proposed mechanism for ARB reversing remodeling becomes inferential.
Val-HeFT provided convincing evidence that additional inhibition of the RAAS with an ARB in heart failure can improve LV structure and function beyond that affected by prescribed therapy, including ACEI or BB alone. Val-HeFT also demonstrated that given the low annual mortality of 9% in the placebo subgroup taking prescribed treatment, it is unlikely that future trials can target mortality as a primary end point. The link between the echocardiographic results and a benefit on the morbidity-mortality end point strongly supports regression of LV remodeling as a surrogate marker for a favorable prognosis, for future design of clinical trials, and for guiding efficacy of heart failure therapy.
Conclusions.
The benefit on outcome in Val-HeFT was accompanied by echocardiographic evidence for regression of LV remodeling. The background therapy subgroup that had an unfavorable outcome had no effect on remodeling. The trial results further illustrate the usefulness of monitoring structural changes in the left ventricle as a guide to long-term efficacy in heart failure treatment. (Appendix)
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APPENDIX
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The Val-HeFT Investigators and Echocardiography Staff included the following: UNITED STATES: ALABAMA: BIRMINGHAM—University of Alabama: R. Bourge, M. F. Aaron, R. L. Benza, B. A. Foley, B. K. Rayburn, G. Perry; University of Alabama Hypertension Program: S. Oparil, D. A. Calhoun, L. J. Dell’Italia, G. Perry, C. Scott-Mays, M. Huelett; Veterans Affairs Medical Center: G. J. Perry, L. Lowe, C. Scott-Mays, M. Huelett; ARIZONA: GILBERT—Advanced Cardiac Specialists: R. Siegel, A. W. Nuttall, B. Barker, M. Chuang, P. L. Underwood, A. Bhaskaran, S. Goodman; SCOTTSDALE—Mayo Clinic Scottsdale: R. W. Lee, H. Loutfi, B. Beilby; TUCSON—Arizona Clinical Research Center: J. E. Boulet, M. A. Adamczyk, L. D. Lancaster, M. C. Morales, B. Dwyer; University of Arizona Heart Center: P. Fenster, K. Kern, L. Foster, N. Cosgrove; Veterans Affairs Medical Center: J. Christensen, D. Shocken, J. R. Parks III, P. Perry, A. Bastian, D. Irons, M. Pigman; CALIFORNIA: CARMICHAEL—Capital Interventional Cardiology: J. Hemphill, S. Baron, D. Fisher, E. Silva; ENCINITAS—San Diego Cardiovascular Associates: G. Dennish, J. W. Myers, J. R. Backman, J. A. Bonanno, M. L. Charlat, D. M. Hill, D. A. Goodman, L. Eastwood, A. Burns, J. Myers, D. Moser, L. Donaghey; ESCONDIDO—Escondido Cardiology Associates, Inc: J. Gorwit, J. H. Detwiler, C. R. Gilbert, D. Mulvihill, D. R. Leahy, R. J. Acheatel, G. Herrara, P. Scott; Palomar Medical Group: R. M. Stein, E. W. Lee, J. J. Lilley, B. W. Meyerhoff, E. A. P. Salada, M. H. Shapiro, J. D. Wolosin, G. Herrara, P. Scott; FRESNO—Veterans Affairs Medical Center: P. C. Deedwania, E. Carbajal, A. Monges; LA JOLLA—Scripps Clinic: D. Costello, H. H. Shively, N. Dalton; LA MESA—Cardiology Medical Group of San Diego: L. W. Sprinkle, M. J. McGreevy, R. K. Goldberg, S. Gerry, S. Sullivan; LARKSPUR—Cardiology Associates of Marin and San Francisco: J. Sklar, J. Adamn, K. Gershengorn, G. Jacobs, A. Kao, E. Shafton, D. Sperling, B. Strunk, M. Wexman, J. Young, W. R. Budge, J. O’Connor; LOMA LINDA—Jerry L. Pettis Veterans Affairs Medical Center: J. T. Heywood, G. Frivold, L. Stoletniy, G. Pauls, P. Applegate, G. Pauls, H Lo; LOS ANGELES—Cedars Sinai Medical Center: S. Khan, R. Davidson, Y. Charuzi, J. Harold, J. Schapira, A. Hickey, N. Buchbinder, I. Geft, B. Samuels, T. Denton, L. Czer, N. Lepor, M. Urman, J. Caren, A. Simonini, K. Drury, M. Weiss, R. Siegel, H. Luo; White Memorial Medical Center: J. W. Allen, F. Y. K. Lau; PASADENA—Huntington Memorial Hospital: W. A. Edmiston, M. T. Ali, G. Conrad, J. L. Easthope, L. S. Herman, M. Luu, P. D. Maher, R. F. Roth, M. P. Smith, K. H. Vogelback, R. H. Onysko, W. A. Edmiston, A. Loos; REDONDO BEACH—Cardiology Associates: B. Jackson, G. Kissel, J. Edelstein, C. Rogers; SAN DIEGO—Cardiology Associates Medical Group: L. Yellen, T. J. Karras, A. D’Santiago; San Diego Cardiac Center: B. Jaski, D. G. Marsh, L. K. Favrot, R. H. Miller, G. B. Mahan, J. B. Gordon, P. M. Hoagland, M. McNeill; Veterans Affairs Medical Center: R. Shabetai, A. S. Maisel, N. Dalton, J. Hope; SANTA MONICA—Pacific Heart Institute: R. F. Wright, F. C. Newton, R. Merz, M. Zatzkis, W. R. Cabeen, P. Pelikan, P. Natterson, G. Dennis; SANTA ROSA—Northern California Medical Associates: P. S. Coleman, G. L. Smith, J. E. Price, T. E Dunlap, D. G. Hopkins, W. D. Bowden, P. Chang-Sing, J. G. Grattan, H. K. Punatar, N. Stefan, J. Fuller; STANFORD—Stanford University Medical Center: M. Fowler, R. Vagelos, M. Larson, I. Schnittger, J. Chao, A. Paloma; CONNECTICUT: NEW HAVEN—Yale University School of Medicine: T. M. Ramahi, F. A. Lee, K. Rohlfs, K. V. Nystrom, T. Young; WEST HAVEN—Veterans Affairs Medical Center: I. Cohen, M. D. Ezekowitz, C. Spector; DISTRICT OF COLUMBIA: Georgetown University Medical Center: Daniel Diver, N. Weissman, C. Robbins; Veterans Affairs Medical Center: S. Singh, R. D. Fletcher; FLORIDA: DAYTONA BEACH—Cardiology Consultants, PA: V. Wilson, R. Lewis, M Crespo; FORT MYERS—Southwest Florida Heart Group: J. O’Bryan, R. H. Davis, R. A. Chazal, S. R. West, E. B. Hoffman, D. R. Schwartz, J. A. Conrad, E. J. Toggart, M. D. Danzig, H. P. Dansby III, M. E. Burton, D. R. Axline, L. A. Kline, L. Moraes-Finglass, W. M. Miles, S. Bukowski, T. O’Brien, J. Conrad; JACKSONVILLE BEACH—Jacksonville Heart Center: T. Hilton, K. Adams, L. Birch, J. Dinerman, P. Farrell, M. Litt, J. Schrank, B. Utset, W. Wainwright, C. Hassel, M. Neibaur, T. Hilton, C. Black; MIAMI—Jackson Memorial Hospital: M. Mayor, S. M. Mallon, R. Charine, J. Bauerlein, J. Bauerlein, E. Forbes; Mount Sinai Medical Center: G. Lamas, C. A. Conde, D. Korn, R. Machado, E. Gorin, E. Hanaberg, G. A. Rojas, M. Garces, P. O. Diaz, J. J. Sanchez, J. L. Marquez, H. Aldrich, A. Colunga, J. Salcedo; ORLANDO—Florida Heart Group: H. Karunaratne, K. G. Reddy, S. Bajaj, A. Kinsella, K. DuMont, L. Fosnaugh; Florida Heart Group PA : M. R. Milunski, R. C. Curry, K. M. Schwartz, C. B. Saenz, W. H. Willis, C. J. Weaver, R. J. Ivanhoe, S. N. Lanza, J. A. Miner, K. Hansen, L. Fosnaugh; M. A. Nocero, T. Trent, L. Roberts; ORMOND BEACH—Cardiology Research Associates: J. Walker, J. E. Carley, D. L. Williams, D. Tracey, J. Watson; ST. PETERSBURG—The Heart Institute: M. McIvor, J. P. Hoche, D. A. Bramlet, J. R. Witt, A. D. Rosenthal, J. W. Walsh, J. R. Post, J. L. Mason, R. C. Sheppard, P. Brald, L. Sens; TAMPA—Veterans Affairs Medical Center: G. Cintron, K. G. Morris, D. Sayad, B. Price; VERO BEACH—Doctors Clinic: J. Anderson, M. Daniels, H. T. Tee, P. Green, D. Dixon; GEORGIA: ATLANTA—Cardiac Disease Specialists PC: S. Beer, H. N. Sacks, W. C. Jacobs, T. Monitz, W. Mashman, B. Lipman, T. Deering, C. Wilmer, L. Berger, D. Lowe, A. Bradley; AUSTELL—Southeast Research Associates: K. Taylor, S. J. Simon, E. I. Swartz, C. B. Hartley II, S. E. Harris, A. Latridis, R. G. Warner, W. L. Ballard, K. O. Rees, E. J. Pope, Jr.; DECATUR—Atlanta Veterans Affairs Medical Center: R. Taylor, F. Daugherty, S. Eison; ILLINOIS: CHICAGO—Northwestern Memorial Hospital: M. Johnson, M. Gheorghiade, P. B. Pfieffer, T. Strzelczyk, M. Rose, B. Schmitz, D. McPhearson, B. Smulevitz; University of Chicago Hospital: Roberto Lang, K. Spencer, A. Bales, E. Kaji, J. Bednarz; HINES—Veterans Affairs Medical Center: Henry Loeb, A. Henrick, S. Reynertson, M. Harris; INDIANA: EVANSVILLE—The Heart Group: Jerry Becker, D. Briddell, C. R. Gest, E. N. Moore, M. K. Sheth, T. R. White, P. R. Dawkins, L. T. Goyal, J. M. Neahring, S. Tatineni, P. Zimmermann, N. De Soyza, M. D. Jordan, J. B. Oak, R. A. Wepsic, J. Becker; INDIANAPOLIS—Roudebush Veterans Affairs Medical Center: L. E. Ford, B. Corya; IOWA: DES MOINES—Iowa Heart Center: W. Wickemeyer, R. R. Rough, M. S. Bissing, R. H. Marcus, P. Carr, L. Melson; IOWA CITY—University of Iowa Hospitals and Clinics: R. M. Oren, T. Noreuil, J. Mehegan, W. Cotts, L. Panther, C. Pies, K. Schneider; KANSAS: WICHITA—Galichia Medical Group: M. H. Bowles, D. Mahoney, S. Campbell; KENTUCKY: LOUISVILLE—Rudd Heart and Lung Center: S. Wagner, B. Dawn, S. Raza, A. Sharma, M. Shepherd, E. Tutson, J. Smith; LOUISIANA: CHALMETTA—Louisiana Heart Center: B. Iteld, R. K. Mautner, M. Bernstein, R. Hallett, P. Nathan, D. Merriweather; MASSACHUSETTS: BOSTON—Beth Israel Deaconess Medical Center: A. J. Burger, M. Charlamb, H. Sherman, M. Burger, J. Beadle, M. McGuire, W. Wilson; Massachusetts General Hospital, G. W. Dec, M. J. Semigran, T. G. DiSalvo, M. Scherrer-Crosbie; New England Medical Center: J. J. Smith, M. A. Konstam, J. E. Udelson, P. G. Bridgman, A. R. Patel, G. Russell, M. D. Rosen, D. A. Portugal; SALEM—Cardiology Physicians Inc.: M. Motta, H. S. Zarren, D. C. Wistran, D. J. Roberts, J. C. Santos, L. S. Block, S. Weatherbee, M. Huston; WORCESTER—University of Massachusetts Medical Center: T. E. Meyer, A. Sweeney-Walsh; MARYLAND: BALTIMORE—Midatlantic Cardiovascular Consultants PA: S. O. Gottlieb, T. Guarnieri, S. Pollock, S. Plantholt, D. Vassar, S. Nolan, F. Morris, D. Zimrin, D. Lowry, L. Black, M. Gregory, J. Lang, T. Able, B. Powell, B. Lampe; University of Maryland School of Medicine: S. Gottlieb, M. L. Fisher, R. Freudenberger, C. M. Krichten, G. Plotnick, K. Roberts; MAINE: PORTLAND—Center for Lipids and Cardiovascular Health: L. M. Kielson, E. Rivas, J. N. Wight Jr., A. Paquette; MICHIGAN: ANN ARBOR—University of Michigan Hospitals: J. M. Nicklas, B. Pitt, B. Bleske, K. Aaronson, F. Pagani, S. Das, P. Rose, A. Larkin, T. Koelling, T. Kolias; FARMINGTON HILLS—Michigan Institute for Heart Failure and Transplant Care: T. B. Levine, A. B. Levine, Godowski, L. Cherro; GRAND RAPIDS—West Michigan Heart: D. Langholtz, W. F. LaPenna, B. Townsend, L. Guider, M. Castro; MINNESOTA: MINNEAPOLIS—University of Minnesota: L. Miller, N. Yar; Veterans Affairs Medical Center: I. Anand, Y. S. Chandrashekhar, S. Ziesche, M. M. Berge, A. Holmstrom, K. Doerfler, D Miller, V. Dant; MISSOURI: COLUMBIA—University of Missouri: K. Aggarwal, H. K. Reddy, A. Nayak, K. Singh, A. Pothula, P. McLaughlin, A. Nayak, G. Campbell, K. Brady, R. Waudby, T. Hirner; ST LOUIS—St. Louis University: D. S. Yip, T. L. Wolford, P. J. Hauptman, R. Costello; Washington University School of Medicine: E. Geltman, M. Rich, J. Rogers, G. Ewald, C. Baumann, P. McCarty; NEW JERSEY: HAWTHORNE—The Heart Lung Center: J. Strobeck, R. Baklajian, J. C. Hannan, R. L. Berkowitz, T. J. Malloy, L Pappa; NEWARK—Newark Beth Israel Medical Center: H. Ribner, M. J. Zucker, D. Bianchi; NEW MEXICO: ALBUQUERQUE—Lovelace Scientific Resources: L. Kuo, M. J. Conway, D. Koster, M. West, F. Kusumoto, A. Singer, S. Ung, R. Federici, R. Gonzales; New Mexico Heart Institute: J. Gundry, M. Shalek, J. Kaplan, P. Donally; Southwest Cardiology Associates: R. DuBroff, R. D. Lueker, E. Palmer, A. B. Sandoval, H. J. White, C. H. Karaian, R. B. Beck, P. T. Cochran, J. W. Benge, W. A. Gray, P. J. Decker, M. R. McGuire, L. A. Nair, D. Sanestivan, S. Jacobs; NEVADA: LAS VEGAS—Clinical Research Center of Nevada: A. D. Steljes, R. Croke, L. Spaccavento, G. Uhl, C. Spielman, M. Ahmed, M. Plon, K. Shah, L. Tirao, M. Snyder, J. Pulidd, E. Caruso, V. Miller; NEW YORK: BRONX—Veterans Affairs Medical Center: L. Baruch, C. Eng, E. Stern, E. Cavusoglu, A. Hameed, J. Duswalt, X. Fann; BUFFALO—Buffalo Cardiology and Pulmonary Associates, PC: J. Corbelli, B. L. Platt, P. George, W. M. Morris, E. J. Spangenthal, J. L. Cobler, R. J. Corbelli, B. G. Reen, R. P. Gatewood, G. E. Matthews, M. M. Merhige, A. J. Bonner, M. Gloss; Buffalo General Hospital, S. P. Graham, R. M. Kohn, A. Lopez-Candales, M. Wilson, D. Drozod; Millard Fillmore Health System: M. F. Wilson, B. H. Sung, S. L. Goldfarb, F. J. Albrecht, M. Khalil, A. D. Gupta, D. Drozod; GARDEN CITY—Cardiovascular Medical Associates: M. Goodman, P. E. Henrick, M. H. Sussman, P. Stein, A. B. Cavanagh, B. D. Sporkin, M. A. Sassower, A. Cavanagh, M. Mackey; MINEOLA—Winthrop University Hospital: R. Steingart, H. Hirsch, G. Macina, M. E. Coglianese, S. Bilodeau, M. Golden; NEW YORK—The Mount Sinai Medical Center: M. L. Kukin, J. Kalman, L. Baruch; STATEN ISLAND—Staten Island University Hospital: T. Costantino, A. C. Cernaianu, L. Lefkovic; NORTH CAROLINA: CHARLOTTE—Mecklenberg Medical Group: D. J. Framm, G. R. Weidner, L. Winchester; DURHAM—Duke University Medical Center: M. Higginbotham, S. D. Russell, R. Page, B. Robert, M. Foster; Veterans Affairs Medical Center: F. Cobb, R. Harsh; RALEIGH—Raleigh Medical Group: R. H. Bilbro, J. Rubino, L. DeJarnette, G. Cheely, V. Wynia, G. Blake, C. Eure, C. Mangano, M. Leithe, J. Jacobs, W. Dunlap, A. Reddy, J. Sinden, J. Thomas, S. Lockhart; OHIO: CINCINNATI—Lander Center: D. Kereiakes T. Broderick, G. Brown, E. Roth, R. Toltzis, C. Abbottsmith, D. Whang, G. Clarke; OKLAHOMA: OKLAHOMA CITY—Plaza Medical Group: J. Anderson, C. Bethea, C. Mulson-Alsip; TULSA—J. Cook, T. K. Hoskison, W. Maples, R. D. Ensley, E. Hunnicutt; Cardiology Of Tulsa, Inc.: R. D. Ensley, J. E. Bare, G. A. Hill, R. L. Irvin, E. J. Morris, J. S. Waters, D. L. Brewer, J. M. Kalbfleisch, C. W. McEntee, S. Scott, J. M. Cassidy, R. W. Lowry, R. D. Okada, M. G. Spain; OREGON: PORTLAND—Oregon Health Sciences University: R. E. Hershberger, R. Ratkovec, A. Kao, K. Crispell, G. Pantley, D. Dutton, R. McDonald, R. Imus; PENNSYLVANIA: HERSHEY—The Milton S. Hershey Medical Center: J. P. Boehmer, D. Davis, D. Silber, V. Reeser, W. Davidson, K. Crajkowski; LANCASTER—Lancaster Heart Foundation: S. Worley, R. Andersen, E. Supple, S. Deron, R Gentzler, J. Ibarra, D. Loss, P. Casale, R. Small, R. Canosa, N. Clark, F. Corbally, D. Gohn, D. Soucier, D. Pfautz; PHILADELPHIA—Temple University: Paul J. Mather, A. Bove, H. Eisen, K. Margulies, I. Pina, S. Rubin, P. Mather, M. Long; University of Pennsylvania: E. Loh, D. DeNofrio, A. Kao, T. Plappert; PITTSBURGH—Allegheny General Hospital: M. Mathier, R. P. Shannon, M. Malkowski, S. Makad; Veterans Affairs Medical Center: M. Amidi, M. Bell, M. DiTommaso, W. Katz, T. Karlhiem; RHODE ISLAND: PROVIDENCE—The Miriam Hospital: A. Sadaniantz, A. F. Parisi, B. Hadi, C. Herlihy, J. Gardner, P. D. Pauls; SOUTH CAROLINA: CHARLESTON—Medical University of South Carolina: G. Hendrix, A. B. VanBakel, K. W. Walker, M. T. Schulz, J. L. Evans, B. D. Owens, C. Diaz, A. Spelling, A. Bell; TENNESSEE: MEMPHIS—The Stern Cardiovascular Center: F. McGrew, S. S. Gubin, W. L. Russo, J. L. Turner, S. Gubin, M. Kuespert; University of Tennesee: K. B. Ramanathan, K. Newman; NASHVILLE—Nashville Veterans Affairs Medical Center: R. Smith, R. Bruce, S. Schilling, B. Fadel, R. Forcek; TEXAS: AMARILLO—PharmaTex Research: G. Friesen, L. Chaffin, J. Osborn, M. Slatton, R. F. Burns, J. Logsdon, V. Fraser, D. Brandt, D. Manchester; AUSTIN—Austin Heart PA: M Rotman, G. Rodgers, R. Gammon, D. Davis, R. Kaminski, C. Murray, S. Strei; HOUSTON—Med-Tech, Inc.: S. El Hafi, L. A. Campos, C. Christa, A. Maldonado; LAKE JACKSON—R/D Clinical Research, Inc.: N. Barahdi, H. Resnick, O. Oandasan, S. Harris, I. Sabrsula, R. Dalal, B. Feaver, J. Veselka, C. Duarte; SAN ANTONIO—The Diagnostic Clinic of San Antonio: J. Liu; TYLER—Tyler Cardiovascular Consultants, PA: F. Navetta, R. J. Carney, D. M. Dick, D. A. Hector, J. D. Jackman, K. B. Kummerfeld, R. B. Meese, R. C. Randall, C. G. Sanford, S. Crispin, F. Kirby, J. Daily, S. Smith; UTAH: SALT LAKE CITY—Jean Brown Associates, Inc.: J. J. Perry, D. Booman, T. Edwards, E. Ganellen, C. Haws, H. Lee, W. Mackie, K. Nielson, D. Rawling, D. Ridges, S. Sharp; VIRGINIA: CHARLOTTESVILLE—University of Virginia School of Medicine: J. Bergin, E. R. Powers, N. Lewis, J. Dent, S. Moos; FALLS CHURCH—Fairfax Hospital: J. O’Brien, J. Kiernan; NORFOLK—Cardiac Services; J. M. Herre, R. Stine, J. Taylor, A. Ciuffo, D. K. Barackman, D. Lipskis, J . Brush, D. Eich, K. Hansen, K. Holt; WASHINGTON: SEATTLE—Summit Cardiology, M. Hall, G. L. Weeks, D. V. Wilkinson, F. M. Tobis, D. C. Warth, H. S. Lewis, M. Yakovlevitch, H. Jiang, K. Pace, M. Ludkin; University of Washington School of Medicine: D. Fishbein, W. Levy, K. O’Brien, R. A. Letterer, A. Stempien-Otero, L. Wu, L. Soine, B. Crane, K. Hardy, W. Hamer, C. Krueger, S. Similech; WISCONSIN: MADISON—University of Wisconsin Hospital and Clinics: C. VanderArk, P. S. Rahko, P. Rocko; MILWAUKEE—C. V. Hughes, M. J. Ptacin, E. Chin; R. Siegel, M. P. Cinquegrani, D. L. Rutlen, Y. Tan, S. K. Mauermann, J. Gosset, S. Zaharova, E. Chin; Outside the United States: AUSTRALIA: ASHFORD—Ashford Specialist Centre: I. Button, B. Ayres, R. Lehman, W. Heddle, L. Zimmet J. Whitford, M. Sheppat, M. Begg; BRISBANE-QUEENSLAND—Princess Alexandra Hospital: P. Garrahy, J. Hill, R. Lim, C. Wood, T. Baglin; EPPING-MELBOURNE—The Northern Hospital: B. Jackson, K. Lee; GARRAN—The Canberra Hospital: I. Jeffery, U. Musial; GEELONG-VICTORIA—Geelong Hospital: J. Amerena, A. Appelbe, K. White; HOBART—Royal Hobart Hospital: A. Thomson, M. Saunders; KIPPARING-REDCLIFFE—Peninsula Specialist Centre: J . Karrasch, M. Wilson, C. Rodgers, C. McLaran, J. Moan; KOGARAH—St. George Hospital: L. Howes, P. Brunker; NEDLANDS—Sir Charles Gairdner Hospital: P. Thompson, P. Stobie, B. McKeown, H. Hankey, M. Sommerville, K. Eldridge; PRAHRAN—Monash Univerisity/Alfred Hospital: H. Krum, P. Bergin, J. Federman, D. Jackson; TASMANIA—Launceston General Hospital: B. B. Singh, A. Lawrence; WOODVILLE—The Queen Elizabeth Hospital: J. Horowitz, M. Worthley, S. Chandy, R. D. Wuttke; BELGIUM: BRUXELLES—Hôpital Universitaire Erasme: S. Degré, J. L. Vachiery, P. Unger; GENK—Hartcentrum Z. O. L. Campus St. Jansziekenhuis: W. Van Mieghem, P. Devusser, P. Vandervoort, P. Noyens, J. Van Lierde, M. Vrolix, J. Eerdekens, R. Reys Kens; LEUVEN—UZ Gasthuisberg: J. Vanhaecke, W. Droogné, J. Van Cleempul; MERKSEM—Jan Palfijnziekenhuis: J. Vanwelden; CZECH REPUBLIC: BRNO—University Hospital: J. Toman, L. Spinarova, P. Hude; HRADEC KRALOVE—Charles University Hospital: V. Pidrman, J. Gregor, R. Pudil, K. Medilek; PLZEN—University Hospital Center of Preventive Medicine: S. Jaroslav, O. Mayer Jr., V. Jankovych; PRAGUE—University Hospital: J Vojacek, J Bultas, J Bruthans, V Vondracek; PRAGUE—Institute of Clinical and Experimental Medicine (Prev. Cardiol.): R. Cifkova, E. Novozámská, M. Jozífová, J. Pitha, P. Fridl; PRAGUE—Institute of Clinical and Experimental Medicine (Cardiol.): J. Widimsky, P. Fridl; DENMARK: AARHUS C—Aarhus Amtssygehus: O. Gõtzsche, B. Ziegler; AARHUS N—Skejby Sygehus: T Toftegard; COPENHAGEN—Frederiksberg Hospital: P. Hildebrandt, S. Galatius, R. Dorte; FINLAND: OULU—Oulu Deaconess Institute: K. Peuhkurinen, M. Niemela; TAMPERE—Tampere University Hospital: S. Majahalme, J. Taurio; TURKU—Turku University Central Hospital: L. M. Voipio-Pulkki, E. Engblok; FRANCE: AMIENS—Hopital Sud: G. Jarry, L. Leborgne, S. Leborgne; DAX—Centre Hospitalier: M. Baudet, J. L. Roynard; MARSEILLE—Hopital La Timone: M. Bory, E. Garcia; MARSEILLE—Hopital Nord: Y. M. Frances; MONTPELLIER—Hôpital Arnaud de Villeneuve: J. M. Davy, M. Ferriere, F. Raczka, M. Pons; MONTROUGE—Gecem: B. Zakine, J. J. Bensoussan, C. Paillole, M. Dahan; PARIS—Hospital du Val de Grace: J. P. Ollivier, R. Richard; Hopital Lariboisière: P. Coumel, F. Azancot, A. Stratiev, P. Bouabid; PARIS—Hôpital Saint Antoine: A. Cohen, B. Buyukoglu; TOULOUSE—Hôpital de Rangueil: M. Galinier, C. Baixas; TUNIS—Hôpital Militaire: M. Guediche, S. Bahroun, H. Haouala, N. Rahal, F. Azouzi; TUNIS—Hôpital La Rabta: M. Zaouali, H. Drissa; GERMANY: BAD-FRIEDRICHSHALL—Kreiskrankenhaus "Am Plattenwald": K. H. Munderloh, S. Winkler, A. Meiser, M. Wirth; BAD-NAUHEIM— Kerckhoff-Klinik–V. Mitrovic, N. Hamel, I. Faude; BERLIN—Franz-Volhard-Klinik: R. Willenbrock, S. Philipp, T. Langevickel; BERLIN—Deutsches Herzzentrum Berlin: V. Regitz-Zagrosek, Grafe; BERLIN—Kardiologische Gemeinschaftpraxis: N. Kokott, C. Weiler; BERLIN—Private Practice: G. Haustein; BERLIN—Private Practice: A. Rouwen, L. Meyerdierks; BERLIN—Private Practice: R. Rummel; BERLIN— Private Practice: D. Koch; BIETIGHEIM-BISSINGEN—Krankenhaus Bietigheim: D. Hey; M. Koeppel; DUDERSTADT—Krankenhaus St. Martini: E. Lopez, F. M. Weiss; ERLANGEN—Universitatsklinikum Erlangen: J. Nixdorff, I. Wilhelm, W. Schuzenmeister; FRANKFURT—Kardiologische Gemainschaftspraxis: M. Dürsch, R. Kunde; HAMELN—Kreiskrankenhaus Hameln: J. Tinnappel, H. Topp; HEILBRONN—Stadtisches Krankenhaus: J. Cyran, A. Rotter, K. H. Hauff; KÖLN—Krankenhaus Köln-Mehrheim: A. Griebenow; LAATZEN—Agnes-Karll-Krankenhaus: T. Matthes, H. Mayer; LEIPZIG— Herzzentrum Leipzig: J. Hambrecht, F. Krauss; LUDWIGSHAFEN—Herzzentrum Ludwigshafen: W. Bergmeier, P. Kilkowski, A. Bangert, J. Kleemann; MAGDEBURG—Stadtisches Klinikum Magdeburg: T. Höfs, H. J. Presser; MARBURG/LAHN—Klinikum der Philipps-Universitat: C. Brilla, D. Toatsch, P. Alter; MÜNCHEN—Deutsches Herzzentrum Munchen: L. Goedel-Meinen, M. Hofmann, J. Horcher, C. Firschke; OFFENBACH—Dr. Schmidt Andor: A. Schmidt, K. Jung, D. Eckhardt; WALDBRÖL—Kreiskrankenhaus Waldbröl: K. O. Bischoff, C. Arbeiter, J. O. Heltzer, D. Mons, B. Helzer; WITTEN—Dr. Muser Edelgard: E. Muser; HUNGARY: BUDAPEST—Hospital "Szent Imre": C. Farsang, E. Szigeti; BUDAPEST—Hospital "Szent János Korhazes Rendelointezet": A Jánosi, M. Németh, L. Mezei; DEBRECEN—Medical University of Debrecen: I. Édes, F. Tibor, P. Erzsébet, SZEGED—Zul Department Medicine University: M. Csanády, T. Foster; ITALY: ANCONA—Ospedale Regionale "Lancisi": R. Mocchegiani, L. Pasetti, A. Budini; BENTIVOGLIO—Ente Ospedaliero: G. Di Pasquale, E. Cerè; BOLOGNA—Policlinico Universitario "S. Orsola-Malpighi": A. Branzi, C. Rapezzi, P. Vassallo, C. Manes; CAGLIARI—Ospedale "San Michele Brotzu": A. Sanna, M. Porcu, M. G. Panzuto, CASARANO—Presidio Ospedaliero "F. Ferrari": G. Pettinati, F. De Santis; CASERTA—Azienda Ospedaliera - Ospedale Civile: G. Corsini, A. Vetrano, M. Catanzaro; CASSANO D’ADDA—Ospedale di Circolo Zappatoni: G. Gibelli, G. Castiglioni, M. Ferrari; CATANZARO—Policlinico "Mater Domini": F. Perticone, G. Ventura, F. Giancotti, C. Cosco; CIVITANOVA MARCHE—Presidio Ospedaliero: C. Massacci, A. Fraticelli, P. Domenella; COMO—Ospedale "Sant’Anna": G. Ferrari, R. Belluschi, E. Butti, F. Ruffa; COSENZA—Ospedale Civile dell’Annunziata: F. Plastina, G. Misuraca, O. Serafini, R. Caporale; CUNEO—Ospedale "Santa Croce": E. Uslenghi, A. Deorsola, F. Margaria; DESIO—Ospedale Provinciale: G. Foti, S. Gramenzi; GUSSAGO—Fondazione "S. Maugeri"-Clinica del Lavoro: A. Giordano, S. Scalvini, E. Zanelli, M. Campana; MAGENTA—Ospedale Civile "Fornaroli": A. Formentini, A. Cavalli, M. Tusa; MESAGNE—Ospedale "San Camillo": V. Santoro, G. Giorda, R. Giaccari; MONTESCANO—Fondazione "S. Maugeri"-Clinica del Lavoro: F. Cobelli, S. Capomolla, E. Traversi, M. Granchini; PADOVA—Azienda Ospedaliera: S. Dalla Volta, L. Cacciavillani, G. M. Boffa, V. Patrizia; PALERMO—Presidio Ospedaliero "Villa Sofia": A. Battaglia, V. Cirrincione, F. Ingrillì, M. Di Francesco; PALERMO—Ospedale "Buccheri La Ferla- Fatebenefratelli": A. Castello, A. M. Schillaci, A. Taormina, G. Americo; PASSIRANA-RHO—Ospedale Civile: C. Schweiger, F. Rusconi, M. Palvarini, I. Belloni; PAVIA—Ospedale Policlinico "San Matteo": L. Tavazzi, A. Gavazzi, C. Campana, C. Inserra, C. Opasich; PERUGIA—Ospedale Policlinico "Monteluce": G. Alunni, E. Bosi, R. Panciarola, . K Savino; PERUGIA—Ospedale " R. Silvestrini": C. Porcellati, M. Del Pinto, P. Verdecchia; PIAZZA ARMERINA—Ospedale Nuovo: B. Aloisi, M. Farruggio; ROMA—Ospedale "San Camillo"-Forlanini-Cesalpino: P. Tanzi, F. Pozzar, S. Petrolati,; ROMA—Ospedale "San Filippo Neri": M. Santini, G. Ansalone, P. Giannantoni; ROMA—Ospedale "San Camillo": E. Giovannini, I. Bisceglia, G. Minardi; ROMA—Ospedale "Santo Spirito": V. Ceci, N. Aspromonte, A. Sestili; SAN PIETRO VERNOTICO—Ospedale "N. Melli": A. Renna, S. Pede, C. Pico; SARZANA—Ospedale "San Bartolomeo": G. Filorizzo D. Bertoli, L. Magliani; SONDALO—Ospedale "E. Morelli": G. Occhi, N. Partesana, P. Bandini; TERMOLI—Ospedale "San Timoteo": D. Staniscia, M. Olivier; TRADATE—Presidio Ospedaliero "L. Galmarini": G. Poggio, S. Lombroso, M. Bignotti; TRADATE—Fondazione "S. Maugeri"–Clinica del Lavoro: R. Pedretti, C. Anzà, A. Laporta, F. Santoro; TRICASE—Ospedale "Cardinale Panico": A. Galati, R. Mangia, A. P. Morciano; TRIESTE—Ospedale Maggiore: G. Sinagra, F. Longaro, I. Tavcar, B. Pinamonti; UDINE—Azienda Ospedale "S. Maria della Misericordia": P. Fioretti, M. C. Albanese, C. Fresco, A. L. Cuzzato, L. Del Mostre; VERUNO—Fondazione Clinica del Lavoro "Salvatore Maugeri": P. Giannuzzi, U. Corrà, F. Scapellato; VILLAFRANCA—Ente Ospedaliero: G. P. Perini, K. Ghebremarian-Tesfau; NORWAY: BERGEN—Cardiologklinik: S. Toft; BODOE—Bodoe: K. T. Lappeg rd; OSLO—Ullevaal Hospital: A. Westheim, T. de Klemsdal, M. Bjorstrõn, S. Solheim, S. Stavnes; STAVANGER—Hjertelaget: K. Dickstein V. Thuseth, A. Heruold, V. Bonarjee; TÖNSBERG—Vestfold Central Hospital: K. Knutsen, G. Fröland, J. E. Otterstad; SOUTH AFRICA: CAPETOWN—Tygerberg Hospital: L. J. Burgess, A. Doubell, H. Prozesky, M. M. Pretorius; Groote Schuur Hospital: P. Commerford, J. E. Stevens; DURBAN—King Edward VIII Hospital: D. P. Naidoo; JOHANNESBURG—Johannesburg General Hospital: P. Manga, E. Klug, D. Smith; SPAIN: BARCELONA—Hospital de la Santa Cruz y San Pablo: A. Bayes de Luna, A. Martinez Rubio, A. Aguilar Llodis, V. Peña Forcada, G. Pons Llado; BARCELONA—Hospital de Valle Hebrón: E. Galve Basilio, A. Mallol, E. Nieto Santa, A. Evangelista; BARCELONA—Hospital Clinico y Provincial de Barcelona: E. Roig, M. Cardona, F. Perez Villa, C. Paré, M. Azqueta, M. Velamazan; BARCELONA—Hospital Cruz Roja de Barcelona: P. Dalmau Jaime, M. Gomez Gerboles, I. Gomez Collado, J. L. Sobrepera; CASTELLÔN—Hospital General de Castellón: J. L. Diago Torrent, C. Guallar, J. Moreno, J. L. Diez; CORDOBA—Hospital Reina Sofia: F. Valles Belsue; GIRONA—Hospital Universitari de Girona Doctor Josep Trueta: R. Masia Martorell, X. Albert, M. J. Perez Ayuso; HOSPITALET DE LLOBREGAT-BARCELONA—Hospital de la Cruz Roja de Hospitalet: J. Gibergans Jorge, O. Guri Baiget, E. H. Espinach; HOSPITALET DE LLOBREGAT-BARCELONA—Hospital Principes de Espaã-Ciutat Sanit. de Bellvitge: N. Manito Lorite, J. Roca Elias, C. Ugartemendia Uranga; LEON—Complejo Hospitalario de Leòn: J Bayón Fernandez, I Iglesias; MADRID—Hospital Ramon y Cajal: E. Asin Cardiel, V. Barrios, A. Garcia Castro, C. Pascual; SANTIAGO DE COMPOSTELA-LA CORUÑA—Hospital General de Santiago de Compostela: M. Gil de la Peña; SWEDEN: BORAS—Medicinska kliniken: C. Wettervik, H. Tygersen, P. Svenningsson; EKSJÖ - Medicinska kliniken: S. Ekdahl, S. Hansen, C. Höglund, G. Lindholm; GÖTEBORG—Sahlgrenska sjuhuset: B. Karlsson, J. Herlitz, A. Samuelsson; HELSINGBORG—Medicinska kliniken: P. Katzman, L. Ljungdahl, G. de Pedis, O. Fredholm; SANDVIKEN—Medicinska kliniken: J. Ellström, H. Brodersson; STOCKHOLM—Stockholm Heart Center: C. Höglund, L. Hjelmaeus, L Nygren; THE NETHERLANDS: AMERSFOORT—Ziekenhuis Eemland (Lokatie De Lichtenberg): B. J. B. Hamer, M. J. M. Cramer, W. Van Koedk; AMSTERDAM—St. Lucas Ziekenhuis: A. R. Willems, W. G. de Voogt, J. Visser, A. Folhers; AMSTERDAM—Onze Lieve Vrouwe Gasthuis: G. J. Laarman, U. D. Heyden, T. Slagbroom; ARNHEM—Ziekenhuis Rijnstate: L. H. J. Van Kempen, W. M. Sieswerdo-Mesman, A. M. de Gier, F. F. Willems; BENNEKOM—Ziekenhuis Gelderse Vallei: F. R. den Hartog, H. J. Schaapma, T. Veldhuis; BREDA—Ignatius Ziekenhuis: P. H. J. M. Dunselman, M. R. P. Baselier; DELFT—Reinier de Graafgasthuis: A. J. A. M. Withagen, D. P. W. Beelen, M. C. Jaleer, I. Nyenhuis de Ruiter; DEVENTER—St. Deventer Ziekenhuizen: H. Groeneveld, D. J. A. Lok, P. W. F. Bruggink, A. de la Porte, E. A. Badings, J. S. Kalfsterman-Lammertink; DORDRECHT—Drechtsteden Ziekenhuis/Lokatie Refaja: Ph. W. Fels, I. Stoel, R. Campfens; DORDRECHT—Merwede Ziekenhuis: P. N. W. M. Breuls, H. Jausen; EINDHOVEN—Catharina Ziekenhuis: H. R. Michels, D. Groot, C. Peels; ENSCHEDE—Medisch Spectrum Twente: P. H. van den Burgh, J. van Es, R. Binnenmars, B. Zinger; GOES—Oosterscheldeziekenhuis: A. H. Liem, R. v Lennep, J. A. J. de Boo, E. Bruyns; GORINCHEM—Beatrixziekenhuis: P. van Rossum, M. Bos, M. Suylekom; GRONINGEN—Martini Ziekenhuis: P. J. L. M. Bernink, J. L. Posma, A. Kloppenberg-Oly, H. Groen; HEEMSTEDE—Spaarne Ziekenhuis: J. C. L. Wesdorp, M. Bruns; HEERLEN—Ziekenhuis De Wever en Gregorius: J. A. Kragten, J. de Warizimont-Henquet, R. Feld, J. Ritzen, J. Kremer, S. Gielen, G. Wÿnantsl, H. van den Burgt; TERNEUZEN—Ziekenhuis Zeeuws-Vlaanderen: G. M. G. Paulussen, R. J. P. Taverne, R. van den Bosche, M. Piefeks; TILBURG—St. Elisabeth Ziekenhuis: N. J. Holwerda, R. van Rijswijk, W. Wonnink; Maria Ziekenhuis (Tweesteden Ziekenhuis): P. C. J. M. Lindner, H. v Kesteren, A. Vet, J. Widdershoven, T. Maes, H. Baars; VELDHOVEN—St. Joseph Ziekenhuis: L. C. Slegers, M. Beganovic, J. Snegers, H. Schaffers. UNITED KINGDOM: NORTH IRELAND, BELFAST—Belfast City Hospital: G. D. Johnston, H. Hale; Royal Victoria Hospital: P. Nicholls, H. Ong, K. Morrison; BOURNEMOUTH—Royal Bournemouth Hospital: A. Rozkovec, C. Cope, A. Whiting, D. Maybe, C. Chase; BRISTOL—Bristol Royal Infirmary: T. R. Cripps, H. Portch, P. Kelly; CAMBRIDGE—Papworth Hospital: L. Shapiro, C. Wisbey; HARROW—Northwick Park Hospital: D. Lubel, S. J. Chugh; LEEDS—Yorkshire Heart Center: L. B. Tan, S. Williams, G. Wharton, S. Sleight, J. Foster; LEICESTER—Leicester Royal Infirmary: I. Squire, D. Barnett, A. McCullough; The Glenfield Hospital, P. J. B. Hubner, S. Gupta, S. Waterfield; LINDLEY-HUDDERSFIELD—Huddersfield Royal Infirmary: R. N. Stevenson, C. Welsh; LIVERPOOL—Broadgeen Cardiothoracic Centre: D. Connelly, M. Jackson, K. Robotham; LONDON—Charing Cross Hospital: A. Coats, J. S. R. Gibbs, G. Badahl,; MANCHESTER—Wythanshawe Hospital: R. Levy, J. Hokney, S. Souttern, D. Tayler; MIDDLESEX—Ealing Hospital: J. S. Kooner, C. McCarthy; Isle of Wight, NEWPORT—St. Mary’s Hospital: A. Baksi, Z. Thomas, C. Elliott; ROTHERHAM-SOUTH YORKSHIRE—Rotherham District General Hospital: M. L. K. Ghosh, O. Otaiku, P. Spencer, D. Dransfield; TELFORD-SHROPSHIRE—The Princess Royal Hospital: M. E. Heber, L. Dixon, K. Nicholas.
EXECUTIVE COMMITEE: Jay N. Cohn, MD (Study Chairman), Susan Ziesche, RN (National Study Coordinator for the U.S.), Tara Bonde (Secretary), Nina Lacis (Secretary); Study Co-Chairman’s Office (Milan)—Gianni Tognoni, MD (Study Co-Chairman), Roberto Latini, MD, Aldo Maggioni, MD (Study Coordinators for non-U.S. centers); Echocardiographic Core Laboratories—Maylene Wong, MD (Los Angeles), Lidia Staszewsky, MD, Alberto Volpi, MD, Roberto Latini, MD, Giuseppina Di Bitetto, Elena Pozzoli (Milan), Christer Höglund, MD, PhD, Lisbeth Nygren (Stockholm); Data Management and Analysis—Enrico Nicolis, MS, Eugenio Santoro, MS, Francesco Livraghi, MS, Simona Barlera, MS, Paolo Capello, BS, Giuseppe Andreoni, PhD (Milan).
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Footnotes
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Supported by a grant from Novartis Pharma, Basel, Switzerland. Dr. Cohn has had research support and consultation arrangements with Novartis Pharmaceuticals, the sponsor of the trial.
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827 - 836.
[Abstract]
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M. Wong, L. Staszewsky, R. Latini, S. Barlera, R. Glazer, N. Aknay, A. Hester, I. Anand, and J. N. Cohn
Severity of left ventricular remodeling defines outcomes and response to therapy in heart failure: Valsartan heart failure trial (Val-HeFT) echocardiographic data
J. Am. Coll. Cardiol.,
June 2, 2004;
43(11):
2022 - 2027.
[Abstract]
[Full Text]
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R. S. McKelvie, J.-L. Rouleau, M. White, R. Afzal, J. B. Young, A. P. Maggioni, P. Held, and S. Yusuf
Comparative impact of enalapril, candesartan or metoprolol alone or in combination on ventricular remodelling in patients with congestive heart failure
Eur. Heart J.,
October 1, 2003;
24(19):
1727 - 1734.
[Abstract]
[Full Text]
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J. N. Cohn, I. S. Anand, R. Latini, S. Masson, Y.-T. Chiang, and R. Glazer
Sustained Reduction of Aldosterone in Response to the Angiotensin Receptor Blocker Valsartan in Patients With Chronic Heart Failure: Results From the Valsartan Heart Failure Trial
Circulation,
September 16, 2003;
108(11):
1306 - 1309.
[Abstract]
[Full Text]
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J.N. Cohn
Val-HeFT: changing the heart failure horizon
Eur. Heart J. Suppl.,
April 1, 2003;
5(suppl_C):
C25 - C28.
[Abstract]
[PDF]
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