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Journal of the American College of Cardiology Vol. 43, No. 11, 2004© 2004 by the American College of Cardiology Foundation ISSN 0735-1097/04/$30.00Published by Elsevier Inc. doi:10.1016/j.jacc.2003.12.052

ffects of Loop Diuretics onyocardial Fibrosis and Collagen

ype I Turnover in Chronic Heart Failureegona Lopez, PHD,* Ramon Querejeta, MD, PHD,‡ Arantxa Gonzalez, PHD,* Eloy Sanchez, MD,‡ariano Larman, MD,§ Javier Dıez, MD, PHD*†

amplona and San Sebastian, Spain

OBJECTIVES This individually randomized, open-label, parallel-group pilot study was designed to test thehypothesis that the ability of loop diuretics to interfere with cardiac fibrosis in chronic heartfailure (CHF) may be different between compounds.

BACKGROUND The apparent mortality and cardiac benefits seen in studies comparing torasemide withfurosemide in CHF suggest that torasemide may have beneficial effects beyond diuresis (e.g.,on the process of cardiac fibrosis).

METHODS Patients with New York Heart Association functional class II to IV CHF received diuretictherapy with either 10 to 20 mg/day oral torasemide (n � 19) or 20 to 40 mg/day oralfurosemide (n � 17), in addition to their existing standard CHF therapy for eight months.At baseline and after eight months, right septal endomyocardial biopsies were obtained toquantify collagen volume fraction (CVF) with an automated image analysis system. Serumcarboxy-terminal peptide of procollagen type I (PIP) and serum carboxy-terminal telopeptideof collagen type I (CITP), indexes of collagen type I synthesis and degradation, respectively,were measured by specific radioimmunoassays.

RESULTS In torasemide-treated patients, CVF decreased from 7.96 � 0.54% to 4.48 � 0.26% (p �0.01), and PIP decreased from 143 � 7 to 111 � 3 �g/l (p � 0.01). Neither CVF nor PIPchanged significantly in furosemide-treated patients. In all patients, CVF was directlycorrelated with PIP (r � 0.88, p � 0.001) before and after treatment. No changes in CITPwere observed with treatment in either group.

CONCLUSIONS These findings suggest that loop diuretics possess different abilities to reverse myocardialfibrosis and reduce collagen type I synthesis in patients with CHF. (J Am Coll Cardiol2004;43:2028–35) © 2004 by the American College of Cardiology Foundation

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oop diuretics, such as furosemide and torasemide, areurrently recommended for the treatment of chronic heartailure (CHF) (1,2). In a recent report of the prospectiveORasemide In Chronic heart failure (TORIC) study

nvolving 1,377 CHF patients, the use of torasemide wasssociated with a lower mortality than furosemide (3).urthermore, it has been reported recently that torasemide

mproves left ventricular (LV) diastolic function in CHFatients to a greater extent than furosemide, despite the facthat torasemide induces a more pronounced stimulation ofhe renin-angiotensin-aldosterone system (4). Because bothiuretics exert similar renal effects (5,6), it is likely thatorasemide has beneficial effects other than diuresis inatients with CHF.Numerous findings, as reviewed elsewhere (7), emphasize

he role of myocardial accumulation of collagen fibers in theeterioration of LV function in CHF. It has been proposedhat myocardial fibrosis is the result of both increased

From the *Area of Cardiovascular Pathophysiology, Centre for Applied Medicalesearch, and the †Department of Cardiology and Cardiovascular Surgery, Universitylinic, School of Medicine, University of Navarra, Pamplona, Spain; ‡Division ofardiology, General Hospital, San Sebastian, Spain; and §Division of Hemodynam-

cs, Guipuzcoa Policlinics, Donostia University Hospital, San Sebastian, Spain.rantxa Gonzalez received a research training grant (00/9296) from the Fondo de

nvestigaciones Sanitarias (FIS), Ministry of Health, Spain. This study was partlyupported by an unrestricted grant from Roche Pharmaceuticals.

Manuscript received November 6, 2003; revised manuscript received December 18,

m003, accepted December 23, 2003.

ollagen synthesis by fibroblasts and unchanged or de-reased extracellular fibrillar collagen degradation (8). It haseen proposed that hemodynamic and nonhemodynamicactors may be responsible for such an imbalance (9). Fornstance, a number of findings suggest that aldosterone maylay a role in myocardial fibrosis (10,11). Furthermore,ecent clinical studies have shown that the addition of theldosterone antagonist spironolactone to the regimens ofatients with heart failure is associated with changes inerum markers of fibrillar collagen turnover, suggesting aecreased formation of these molecules (12,13). Interest-ngly, it has been shown that torasemide, but not furo-emide, interferes with the secretion and receptor-ligandinding of aldosterone (4,14,15). We have therefore hy-othesized that torasemide may interfere with mechanismsnvolved in alterations of fibrillar collagen turnover and

yocardial fibrosis in patients with CHF. To test thisypothesis, the present study was designed to comparehanges in the fraction of myocardial volume occupied byollagen, or collagen volume fraction (CVF), and the serumoncentrations of the carboxy-terminal peptide of procolla-en type I (PIP) and the carboxy-terminal telopeptide ofollagen type I (CITP), indexes of collagen type I synthesisnd degradation, respectively (16,17), in CHF patientseceiving either torasemide or furosemide as diuretic treat-

ent. The primary end point was the change in CVF of

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ndomyocardial biopsies from baseline to eight months, andhe secondary end point was the change in serum concen-rations of PIP and CITP.

ETHODS

atients and study protocol. This was an individuallyandomized, open-label, parallel-group pilot study. All sub-ects gave written, informed consent before participating inhe study. The investigation conformed to the principlesutlined in the Helsinki Declaration. All patients were seent the General Hospital (San Sebastian), and the biopsiesere obtained at the Guipuzcoa Polyclinic (San Sebastian).oth centers are integrated in the Donostia Universityospital, and the study protocol was approved by the

nstitutional Review Committee of the Donostia Universityospital.The study population consisted of 39 Caucasian patients

ith different cardiomyopathies. The diagnosis of heartailure syndrome was made on a clinical basis, by theresence of at least one major and two minor criteria of theramingham Study (1). In addition, the heart failure diag-osis was reinforced by the presence of a depressed ejectionraction (EF) and/or Doppler signs of diastolic dysfunctionn all patients. Furthermore, hemodynamic evidence of

yocardial failure was obtained in each patient by measur-ng elevated LV end-diastolic pressure and pulmonaryapillary wedge pressure (�12 mm Hg in both cases). Afterstablishing the diagnosis of heart failure, the patient’slinical status was assessed according to his or her extent ofisability, according to the New York Heart AssociationNYHA) functional classification (18).

All patients initially selected had a previous diagnosis ofYHA functional class II to IV heart failure in accordanceith the aforementioned criteria. In addition, they had been

eceiving standard heart failure treatment (loop diuretic plusn angiotensin-converting enzyme [ACE] inhibitor or an-iotensin type I receptor antagonist plus beta blocker) forhe previous six months when enrolled. Thus, they wereonsidered as patients having CHF. Patients definitivelynrolled were those who did not present with exclusionriteria (previous acute myocardial infarction, significantalvular disease, diabetes mellitus, treatment with spirono-

Abbreviations and AcronymsACE � angiotensin-converting enzymeCHF � chronic heart failureCITP � carboxy-terminal telopeptide of collagen type ICVF � collagen volume fractionDT � deceleration timeEF � ejection fractionKLV � left ventricular chamber stiffnessLVMI � left ventricular mass indexNYHA � New York Heart AssociationPIP � carboxy-terminal peptide of procollagen type I

actone for at least one year before enrollment, significant P

lectrolyte disturbances, severe ventricular arrhythmia, com-lete atrioventricular block and dyspnea due to lung disease,nd conditions associated with alterations in serum levels ofIP, such as alcoholic liver disease, metabolic bone disease,nd hyperthyroidism).

No washout phase was performed to ensure continuouseart failure treatment. Patients were randomly assigned toeceive either torasemide or furosemide. After randomiza-ion, 20 patients were assigned to 10 to 20 mg/day to-asemide (torasemide group) and 19 patients to 20 to 40g/day furosemide (furosemide group) for eight months.hese doses have been shown to be comparable in terms ofiuretic effect (19). Existing salt intake restriction (4 g/day)nd concomitant CHF medication were continued duringhe study, with the exception of aldosterone antagonists,hich were not permitted during the study. We chose a

reatment period of eight months, just long enough to allowhe removal of a significant amount of collagen from theyocardium, in keeping with the half-life of fibrillar colla-

en (20).At baseline and after eight months of treatment, a

umber of procedures were performed to assess differentarameters.ssessment of pressures. Systolic and diastolic blood pres-

ures were monitored in a sitting position at each visit by usef standard cuff equipment. Type I and V phases of theorotkoff sounds were used; three measurements werebtained in each patient, at 5-min intervals, and averaged.Left ventricular end-diastolic pressure and pulmonary

apillary wedge pressure were measured with a microma-ometer catheter system during the angiographic examina-ion, before the biopsy was taken.

ssessment of LV mass and function. Two-dimensionalchocardiograms, targeted M-mode recordings, and Dopp-er ultrasound measurements were obtained in each patient.eft ventricular mass was measured, and the left ventricularass index (LVMI) was calculated, as previously described

21). The following pulsed Doppler measurements werebtained: maximum early transmitral velocity in diastoleVE); maximum late transmitral velocity in diastole (VA);he deceleration time of the early mitral filling wave (DT);nd isovolumic relaxation time. Left ventricular chambertiffness (KLV) was calculated according to the followingormula (22,23): KLV � (0.07/DT)2, where DT was calcu-ated as the time from the peak of the E wave to theero-velocity intercept of the regression line of the E-waveelocity deceleration profile (24). Ejection fraction wasalculated from the measurements performed in aechnetium-99m ventriculography (multigated acquisitioncan) (25). Diastolic heart failure was defined as an EF0.50, as well as alterations in the VE/VA ratio, isovolumic

elaxation time, and/or DT (26). Systolic heart failure wasefined as an EF �0.50.iochemical determinations. Serum potassium and serum

reatinine were determined by standard laboratory methods.

lasma aldosterone was measured by radioimmunoassay

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2030 Lopez et al. JACC Vol. 43, No. 11, 2004Loop Diuretics and Myocardial Fibrosis June 2, 2004:2028–35

sing a commercial kit. Serum PIP was determined byadioimmunoassay, according to a method previously de-cribed (27). The inter- and intra-assay variations foretermining PIP were 7% and 3%, respectively. The sensi-ivity (lower detection limit) was 1.20 �g/l of PIP. SerumITP was determined by radioimmunoassay, according to aethod previously described (28). The inter- and intra-

ssay variations for determining CITP were both �8%. Theensitivity (lower detection limit) was 0.50 �g/l of CITP.

istomorphologic study. Transvenous endomyocardialiopsies were taken from the middle area of the interven-ricular septum with a Cordis 96-cm (7F) bioptome, underuoroscopic guidance after angiographic examination, asreviously reported (21). Up to three biopsies were taken inach intervention. The rationale for the use of this proce-ure is based on the previous finding that patchy fibrosisresent in the septum in postmortem tissue from humanearts is representative of fibrosis existing in the free wall29). The biopsy procedure was well tolerated in all cases.

istologic evaluation was performed as previously reported21). Collagen volume fraction was determined by quanti-ative morphometry with an automated image analysisystem (AnalySYS, Soft Imaging System GmbH, Hammer,ermany) in sections stained with collagen-specific picro-

irius red (sirius red F3BA in aqueous picric acid). Theistomorphologic study was performed by a pathologistlinded to the other characteristics of the patients undertudy.tatistical analysis. Differences in parameters at baselinend after treatment between CHF patients treated withither torasemide or furosemide were tested by the Studenttest for unpaired data once normality was demonstrated

Shapiro-Wilks test); otherwise, a nonparametric testMann-Whitney U test) was used. Differences in parame-ers before and after treatment within each group of patientsere tested by the Student t test for paired data onceormality was demonstrated (Shapiro-Wilks test); other-ise, a nonparametric test (Wilcoxon test) was used. Cat-

gorical variables were analyzed by the chi-square Fisherxact test when necessary. The correlation between contin-ously distributed variables was tested by univariate regres-ion analysis. Data are expressed as the mean value � SEM.

value of p � 0.05 was considered statistically significant.

ESULTS

atient compliance and baseline characteristics. At thend of the treatment period, patients in the torasemideroup (n � 19) and the furosemide group (n � 17) receivedean daily dosages of 10.6 � 0.6 mg and 32.2 � 3.2 mg,

espectively. Baseline medications other than loop diureticsere maintained unchanged during the treatment period in

he two groups of patients. No adverse effects or complica-ions occurred during the study in either group.

During the treatment period, we observed a small drop-

ut rate of patients at their own request; one patient in the m

orasemide group and two patients in the furosemide groupithdrew consent.Baseline clinical characteristics were compared for pa-

ients who completed the study (Table 1). No significantifferences in clinical parameters were observed between theroups in the parameters tested. Although baseline values ofVF, PIP, and CITP were similar in the two groups ofatients, they were well above the control values for thesearameters reported by our group in healthy subjects21,27,28,30).

The CVF tended to be higher in patients with diastolicHF than in patients with systolic CHF in the two groups

furosemide group: 7.76 � 1.34% vs. 6.97 � 1.08%;orasemide group: 8.32 � 0.55% vs. 7.47 � 1.01%), but theifferences did not reach statistical significance.ffects of treatment. Although CVF decreased in the

orasemide group (7.96 � 0.54% vs. 4.48 � 0.26%, p �.01), it remained unchanged in the furosemide group (7.29

0.98% vs. 6.47 � 0.74%, p � NS) (Fig. 1). In addition,VF after treatment was lower (p � 0.005) in the to-

asemide group than in the furosemide group. Figure 2llustrates treatment-induced changes in myocardial fibrosisn one representative patient from each group.

The effect of torasemide on CVF was more intense inatients with diastolic CHF (final value of 4.37 � 0.21%, p

0.001) than in patients with systolic CHF (final value of.81 � 0.53%, p � 0.05). The effects of furosemide on CVFere similar in patients with diastolic CHF (final value of.66 � 1.16%, p � NS) than in patients with systolic CHFfinal value of 6.10 � 0.82%, p � NS).

Administration of torasemide was associated with aeduction in the serum concentration of PIP (143 � 7 �g/ls. 111 � 3 �g/l, p � 0.01) (Fig. 3). In contrast, serum PIPid not change after treatment in the furosemide group (133

12 �g/l vs. 133 � 7 �g/l, p � NS) (Fig. 3). Serum PIPeasured after treatment was lower (p � 0.01) in the

orasemide group than in the furosemide group. A directorrelation was found between serum PIP and CVF (y �8.08 � 9.41x, r � 0.880, p � 0.001) in all CHF patientsefore and after treatment (Fig. 4).As shown in Figure 5, serum CITP remained unchanged

fter treatment in the torasemide group (5.16 � 0.84 �g/ls. 5.14 � 0.70 �g/l) and the furosemide group (4.89 �.92 �g/l vs. 5.26 � 0.81 �g/l). No correlation was foundetween serum CITP and CVF.As reported in Table 1, the number of patients showing

mprovement of at least one grade in NYHA functionallass was greater (p � 0.05) in the torasemide group than inhe furosemide group. The KLV values showed a nonsignif-cant trend toward a decrease in torasemide- but noturosemide-treated patients. The EF values showed a non-ignificant trend toward an increase in torasemide- but noturosemide-treated patients. Plasma levels of aldosteroneemained unchanged with treatment in the two groups ofHF patients. Changes induced by treatment in the re-

aining parameters tested were similar in torasemide- and

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2031JACC Vol. 43, No. 11, 2004 Lopez et al.June 2, 2004:2028–35 Loop Diuretics and Myocardial Fibrosis

urosemide-treated CHF patients. Furthermore, the finalalues of these parameters were similar in the two groups ofatients.

ISCUSSION

ffects on myocardial fibrosis. The main finding of thistudy is that long-term administration of either torasemider furosemide is associated with different effects on myocar-ial fibrosis in CHF patients.Fibrosis probably plays an important role in diastolic

ysfunction and systolic pump function (9), and it is one ofhe structural substrates for fatal arrhythmogenicity (31),

Table 1. Effects of Treatment on Parameters AFinished the Study

Parameter

Furosemide

At Baseline A

Age (yrs) 63 � 3Gender (M/F) 13/4Body weight (kg) 76 � 3Causes of CHF

HHD 10IHD 4IDCM 2Alcoholism 1

Types of CHFDiastolic 8Systolic 9

MedicationsACEIs or ARAs 17Beta-blockers 17Digoxin 5Diuretics

Furosemide 10Torasemide 1Spironolactone 0Thiazide � amiloride 4

Blood pressureSystolic (mm Hg) 140 � 4Diastolic (mm Hg) 88 � 2

Hemodynamic parametersLVEDP (mm Hg) 19 � 2PCWP (mm Hg) 16 � 2

Cardiac parametersLVMI (g/m2) 166 � 20KLV (mm Hg/ml) 0.14 � 0.02EF (%) 38 � 4

NYHA functional class*I —II 5III 11IV 1

Blood parametersPotassium (mmol/l) 4.52 � 0.10Creatinine (mg/dl) 1.08 � 0.05Aldosteronel (pg/ml) 125 � 25

*p � 0.01 for changes in NYHA class after treatment †p � 0.01or number of patients.

ACEIs � angiotensin-converting enzyme inhibitors; ARAs� ejection fraction; HHD � hypertensive heart disease; IDCMKLV � left ventricular chamber stiffness; LVEDP � left venNYHA � New York Heart Association; PCWP � pulmonar

hus playing a major role in the progression of heart failure

nd sudden death. We (30,32) and others (33,34) havehown that a reduction of myocardial fibrosis is associatedith improvement of LV function parameters in hyperten-

ive patients receiving long-term treatment with differentntihypertensive agents. Our findings that torasemide exertsn antifibrotic effect in CHF patients, whereas furosemideoes not, may be related to the greater improvement ofYHA functional class observed in torasemide-treatedHF patients than in those treated with furosemide. This is

upported by changes in parameters assessing cardiac func-ion (e.g., KLV and EF). Although these were not statisti-ally significant, overall changes are consistent with theonclusion that torasemide, but not furosemide, exerts

sed in Chronic Heart Failure Patients Who

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iotensin receptor antagonists; CHF � chronic heart failure; EFpathic dilated cardiomyopathy; IHD � ischemic heart disease;end-diastolic pressure; LVMI � left ventricular mass index;

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eneficial effects on myocardial function in the hearts ofHF patients. This can be of particular interest in diastolicHF, as suggested by our observation that the ability of

orasemide to reduce myocardial fibrosis tended to be highern patients with diastolic CHF than in those with systolicHF. It is clear that further studies enrolling larger samplesf patients are required to test this possibility.

igure 1. Effects of furosemide (n � 17) and torasemide (n � 19) onollagen volume fraction (CVF) in patients with chronic heart failure. NS

nonsignificant.

igure 2. Histologic sections of a myocardial biopsy specimen from a patianel) treatment with furosemide. Histologic sections of a myocardial biops

reatment with torasemide. (Picrosirius red stain; magnification �20.) CVF �

Although a similar reduction in blood pressure wasttained in the two groups of CHF patients after treatment,nly torasemide-treated patients exhibited a significanteduction in myocardial fibrosis. Therefore, the possibilityxists that the ability of torasemide to decrease myocardialbrosis in CHF patients is not only linked to diminishedechanical overload but may also be related to interference

ith chronic heart failure before (upper left panel) and after (upper rightimen from a patient before (lower left panel) and after (lower right panel)

igure 3. Effects of furosemide (n � 17) and torasemide (n�19) on serumarboxy-terminal peptide of procollagen type I (PIP) in patients withhronic heart failure. NS � nonsignificant.

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2033JACC Vol. 43, No. 11, 2004 Lopez et al.June 2, 2004:2028–35 Loop Diuretics and Myocardial Fibrosis

ith humoral profibrotic factors such as aldosterone (10,11)nd angiotensin II (35). Although recent experimental (14)nd clinical (4) findings show that torasemide, but noturosemide, inhibits the secretion of aldosterone, dataerein reported do not support the ability of torasemide toiminish plasma levels of this hormone. Nevertheless, theossibility remains that, as shown in in vitro studies,orasemide blocks the binding of the hormone to itsineralocorticoid receptor (15). On the other hand, it has

een reported that, in vitro, torasemide, but not furosemide,nhibits angiotensin II-stimulated signaling pathways inascular cells, whereas furosemide does not (36,37). Alter-atively, torasemide may stimulate antifibrotic humoralactors such as prostacyclin (38,39). In fact, it has beeneported that in patients with CHF, torasemide stimulateshe release of prostacyclin to a greater extent than doesurosemide (40). Clearly, further studies are required tonvestigate the precise mechanism(s) of the antifibroticffect of torasemide in CHF patients.ffects on collagen type I turnover. A second finding of

his study is that the synthesis of collagen type I molecules,s assessed by the serum level of PIP, is reduced after

igure 4. Direct correlation (y � 68.08 � 9.41x) between collagen volumeraction (CVF) and serum carboxy-terminal peptide of procollagen type IPIP) in patients with chronic heart failure before and after treatment.

igure 5. Effects of furosemide (n � 17) and torasemide (n � 19) onerum carboxy-terminal telopeptide of collage type I (CITP) in patients

mith chronic heart failure. NS � nonsignificant.

reatment in torasemide-treated CHF patients, but not inurosemide-treated CHF patients.

The 100-kd C-peptide PIP is freed during the extracel-ular processing of procollagen type I into the fibril-formingollagen type I molecules (41). The released peptide isound in an immunochemically intact form in blood. Aertain amount of clinical and experimental evidence sup-orts the notion that the serum concentration of PIP reflectshe rate of extracellular synthesis of collagen type I (9,42).ue to its pharmacologic properties (5,43), torasemide does

ot seem to be able to interfere with the hepatobiliarylimination of PIP. Thus, our finding that serum PIPiminishes in torasemide-treated CHF patients suggestshat this agent inhibits the extracellular synthesis of collagenype I molecules.

A number of observations have led to the proposal thathe increased production of PIP is associated with exagger-ted myocardial deposition of collagen type I fibers inardiac diseases (44–46). This is further reinforced by theorrelation found here between CVF and PIP in all CHFatients before and after treatment. It is thus tempting topeculate that the ability of torasemide to inhibit the cardiacynthesis of collagen type I might be involved in its capacityo reduce myocardial fibrosis in CHF patients.

The 12-kd, cross-linked C-terminal telopeptide CITP,hich results from the cleavage of collagen type I by

ollagenase, is found in an immunochemically intact form inlood (47). On the basis of a number of clinical andxperimental observations, it has been suggested that theerum concentration of CITP reflects the rate of extracel-ular degradation of collagen type I (17,42). Because circu-ating CITP is excreted by glomerular filtration, it isnlikely that torasemide modifies the serum concentrationf this peptide through changes in its rate of renal clearance.hus, the tendency toward increased CITP, despite theecrease in PIP, observed in torasemide-treated CHF pa-ients suggests that this compound stimulates the degrada-ion of collagen type I fibers and tends to restore thequilibrium between collagen type I synthesis and degrada-ion in CHF patients.tudy limitations. This was an individually randomized,pen-label, parallel-group pilot study involving a relativelymall number of patients. However, because of the nature ofhe hypothesis under investigation, this design is appropri-te. While appreciating that therapy with ACE inhibitors orngiotensin receptor antagonists and beta-blockers mayave influenced the main parameters tested, one mustonsider that, as standard therapies for CHF, it would benreasonable to withdraw any of them for the purposes ofhis investigation, and in this study, the groups werealanced for these therapies at baseline.As picrosirius red binds to collagen molecules other than

ype I, such as type III, and an excess of collagen type IIIeposition occurs in the myocardium of patients with CHF8), we cannot exclude the possibility that the changes in

yocardial fibrosis found in our patients are also caused by

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2034 Lopez et al. JACC Vol. 43, No. 11, 2004Loop Diuretics and Myocardial Fibrosis June 2, 2004:2028–35

hanges in the deposition of fibril-forming collagen type IIIolecules.onclusions. We have shown, for the first time, that

ong-term treatment with different loop diuretics may havevariable impact on myocardial fibrosis in CHF patients. In

act, although torasemide-treated patients exhibited a re-uction of myocardial collagen accumulation and a diminu-ion of collagen type I synthesis, furosemide-treated patientsid not. Further studies are required to definitively provehat torasemide possesses cardioreparative properties that, inurn, may provide an additional benefit, on top of ACEnhibitors or angiotensin receptor antagonists and beta-lockers, in CHF patients receiving this agent.

eprint requests and correspondence: Dr. Javier Dıez, Area deisiopatologıa Cardiovascular, CIMA, Facultad de Medicina,/Irunlarrea 1, 31080 Pamplona, Spain. E-mail: jadimar@unav.es.

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3. Cosın J, Dıez J. Torasemide in chronic heart failure: results of theTORIC study. Eur J Heart Fail 2002;4:507–13.

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5. Broekhuysen J, Deger F, Douchamps J, Ducarne H, Herchuelz A.Torasemide, a new potent diuretic: double-blind comparison withfurosemide. Eur J Clin Pharmacol 1986;31 Suppl:29–34.

6. Murray MD, Deer MM, Ferguson JA, et al. Open-label randomizedtrial of torasemide compared with furosemide therapy for patients withheart failure. Am J Med 2001;111:513–20.

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