Myocardial fibrosis in chronic kidney disease: potential benefits of torasemide

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1 & 2008 International Society of Nephrology review Myocardial fibrosis in chronic kidney disease: potential benefits of torasemide Begoña López 1, Arantxa González 1, Nerea Hermida 1, Concepción Laviades 2 and Javier Díez 1,3 1 Division of Cardiovascular Sciences, Center of Applied Medical Research, University of Navarra, Pamplona, Spain; 2 Section of Nephrology, San Jorge General Hospital, Huesca, Spain and 3 Department of Cardiology and Cardiovascular Surgery, University Clinic, University of Navarra, Pamplona, Spain Interstitial and perivascular fibrosis is a constant finding in heart biopsies and necropsy studies in patients with chronic kidney disease and hypertension, namely in those with left ventricular hypertrophy. Fibrosis is the result of the unbalance between exaggerated collagen synthesis and unchanged or depressed collagen degradation. A number of factors linked to hypertension and the progressive deterioration of renal function may facilitate such an unbalance. Patients with chronic kidney disease and hypertension are prone to develop diastolic heart failure, and myocardial fibrosis has been suggested as a major determinant of disturbances in diastolic function in these patients. Thus, the therapeutic strategies aimed to reduce cardiac fibrosis may provide a particular cardioprotective benefit in patients with chronic kidney disease. In this regard, recent data suggest that the loop diuretic torasemide reduces myocardial fibrosis and ameliorates cardiac function in patients with chronic heart failure through local mechanisms beyond its effects on the renal excretion of fluid and electrolytes and systemic hemodynamics. ; doi: /ki KEYWORDS: arterial hypertension; left ventricular hypertrophy; myocardial remodeling; fibrosis; heart failure; torasemide Correspondence: Javier Díez, Área de Ciencias Cardiovasculares, Edificio CIMA, Av. Pío XII, 55, Pamplona 31008, Spain. jadimar@unav.es MYOCARDIAL REMODELING IN CHRONIC KIDNEY DISEASE General aspects The three lesions constitutive of the structural remodeling of the myocardium (e.g., cardiomyocyte hypertrophy, myocardial fibrosis, and thickening of the intramural arteries and arterioles) are a constant finding in heart biopsies and necropsy studies in patients with chronic kidney disease (CKD), namely in those with arterial hypertension and left ventricular (LV) hypertrophy. 1,2 Myocardial fibrosis is the consequence of an excessive accumulation of collagen fibers, mainly type I, within the interstitium and around the intramyocardial arteries and arterioles (Figure 1). 3 The accumulation of collagen type I fibers is the result of the imbalance between its exaggerated synthesis by cardiac fibroblasts and myofibroblasts, and its unchanged or depressed degradation by extracellular matrix metalloproteinases. 3 A number of mechanical and humoral factors stimulated during the development and progression of CKD may be responsible for such an imbalance. The clinical evidence available suggests that whereas some of these factors start to operate already from the initial stages (e.g., hemodynamic overload, oxidative stress, inflammation, excess of cytokines such as cardiotrophin-1 and transforming growth factor-b 1 or TGF-b 1 ), others act preferentially in more advanced stages of CKD (anemia, hyperphosphatemia, excess of parathormone, vitamin D deficit, and uremic toxins). 4 It is likely that synergistic events may occur between the mentioned factors leading to redundant mechanisms of myocardial damage. For instance, initial stimulation in myocardial production of the cardiac growth factor cardiotrophin-1, in response to the mechanical overload imposed by hypertension to the myocardium, 5 may further increase in response to anemia-related myocardial hypoxia. 6 Clinical impact The prevalence of LV hypertrophy and diastolic dysfunction is higher in patients with CKD than in patients without CKD, and it increases as CKD progresses (Figure 2) One mechanistic explanation for this association can be that CKD facilitates the development of myocardial fibrosis, which in turn, impairs LV diastolic filling. 11 In fact, it has been reported that myocardial fibrosis, as assessed with S19

2 r e v i e w B López et al.: Myocardial fibrosis in chronic kidney disease incremental prognostic value for all-cause mortality and cardiovascular death beyond the standard clinical, biochemical, and dialysis parameters and echocardiographic measurements. In patients with CKD, diastolic HF can be present as severe intolerance to physical exertion, and it may even lead to acute pulmonary edema or sudden intradialysis hypotension in dialyzed patients. 9 In patients with CKD, the mortality from diastolic HF is higher than that from systolic HF with decreased ejection fraction. 19 In addition to being associated with diastolic HF in patients with CKD, hypertensive heart disease is associated with an increased risk for aortic valve dysfunction, ventricular arrhythmias, atrial fibrillation, and worsening of a coexistent coronary heart disease. 20,21 Figure 1 Myocardial fibrosis in chronic kidney disease. Microscopic image of the myocardium of a patient with stage 3 chronic kidney disease, arterial hypertension and left ventricular hypertrophy showing interstitial (arrow) and perivascular (arrowhead) deposition of collagen fibers stained with picrosirius red. (Original magnification 20.) 14% 86% Stage 1 Normal TDI parameters 44% 46% 38% 62% Stages 2 and 3 Stages 4 and 5 Altered TDI parameters Figure 2 Diastolic dysfunction in chronic kidney disease. Prevalence of diastolic dysfunction, as assessed by tissue Doppler imaging, in the different stages of chronic kidney disease. TDI, tissue Doppler imaging. (Adapted from de Almeida et al. 10 ) endomyocardial biopsy, 4 echocardiography with integrated backscatter, 12,13 magnetic resonance imaging, 14 and serum biomarkers of collagen type I deposition, 12,13,15 is higher in hypertensive patients with CKD compared with hypertensive patients without CKD. Furthermore, the severity of fibrosis increases with the stage of CKD. 4 Myocardial fibrosis has been shown to be associated with increased LV stiffness in hypertensive patients, 16 and it has been recently shown that increased stiffness determines augmented LV end-diastolic pressure and impaired LV filling in patients with diastolic heart failure (HF). 17 Recently, it has been reported that LV filling pressure, as estimated by the early mitral inflow velocity to peak mitral annulus velocity (E/E m ) ratio, was abnormally elevated in 62% of patients with stage 5 CKD. 18 It is interesting to note that, during a median follow-up of 48 months, the E/E m ratio emerged as an independent predictor of all-cause mortality and cardiovascular death in a multivariate Cox regression analysis. In addition, the E/E m ratio added significant TORASEMIDE IN PATIENTS WITH CKD is a high-ceiling loop diuretic that has been shown to reduce extracellular fluid volume and blood pressure in hypertensive patients with CKD. 22 In addition, torasemide is the diuretic with the greatest oral bioavailability in advanced stages of CKD. 23 Therefore, torasemide is currently recommended for the treatment of patients with CKD either with preserved or reduced glomerular filtration rate. 24 Antifibrotic effect of torasemide Several recent clinical studies have shown that torasemide possesses the capacity to protect the heart through the reduction of myocardial fibrosis. In a report of the prospective In Chronic HF study involving 1377 patients with chronic HF, the use of torasemide was associated with a lower mortality than furosemide. 25 Furthermore, it has been reported recently that torasemide improves LV diastolic function in chronic HF patients to a greater extent than furosemide. 26 As both diuretics exert similar renal effects, 27,28 it is likely that torasemide has beneficial effects other than diuresis in patients with chronic HF. In this regard, we reported recently that long-term treatment with different loop diuretics may have a variable impact on myocardial fibrosis and fibrillar collagen biosynthesis in chronic HF patients. 29 In fact, although torasemidetreated patients showed decreased myocardial collagen accumulation, furosemide-treated patients did not (Figure 3). In addition, a greater improvement of the New York Heart Association functional class and of parameters assessing cardiac function was observed in torasemide-treated patients than in those treated with furosemide. Experimental support to these findings has been provided by studies showing that torasemide, but not furosemide, reduced myocardial fibrosis and improved myocardial function parameters and survival rate in rats with HF secondary to myosin-induced autoimmune myocarditis. 30,31 Which are the mechanisms involved in the cardiac antifibrotic effect of torasemide? In a recent study, we found S20

3 B López et al.: Myocardial fibrosis in chronic kidney disease r e v i e w P < 0.01 P<0.01 Decrease of CVF (%) Furosemide Decerase of PCP activation (%) Furosemide Figure 3 Effects of loop diuretics on myocardial fibrosis in chronic heart failure. Effects of torasemide and furosemide on myocardial collagen volume fraction (CVF) (left panel) and procollagen type I carboxy-terminal proteinase (PCP) activation (right panel) in patients with chronic heart failure. (Adapted from López et al. 29,32 ) that the activation of the enzyme procollagen type I carboxyterminal proteinase (PCP), which catalyzes the extracellular conversion of the precursor procollagen type I into the fibrilforming molecule collagen type I, was abnormally increased in the myocardium of HF patients, whereas it decreased in torasemide-treated patients and remained unchanged in furosemide-treated patients (Figure 3). 32 In addition, changes in PCP activation were positively correlated with changes in myocardial collagen content in patients receiving torasemide. In this regard, it is important to note that aldosterone 33 and TGF-b 34 1 activate PCP in fibrogenic cells and that torasemide, but not furosemide, has been shown to reduce the expression of aldosterone synthase and TGF-b 1 in the myocardium of rats with HF. 30,31 Furthermore, transcardiac extraction of aldosterone has been reported to be reduced in HF patients treated with torasemide, but not in HF patients treated with furosemide. 35 Chemical inhibitors of PCP activity that are nontoxic to cells in culture have been developed. These inhibitors are hydroxamic acid derivatives that specifically bind the active site of the zinc atom of PCP and therefore inhibit enzyme activity. 36 It is interesting to note that, whereas torasemide possesses a zinc ligand residue, furosemide does not. 37 Thus, this chemical difference may add another mechanism through which torasemide, but not furosemide, may inhibit PCP and this, in turn, may result in the reduced formation of fibril-forming collagen type I molecules and fibrosis. Future developments A new torasemide prolonged release (PR) formulation has been recently developed. In two pharmacokinetic studies comparing both torasemide-pr and the already available immediate release (IR) formulation, 38,39 both formulations showed similar systemic exposures, although torasemide-pr had a proportionally higher area under curve than torasemide-ir. High maximum plasma concentration was significantly lower with torasemide-pr than with torasemide- IR, and time to peak maximum plasma concentration was significantly lower with torasemide-pr than with torasemide-ir. The clinical efficacy of torasemide-pr versus torasemide- IR was compared in a randomized noninferiority doubleblind trial performed in patients with newly diagnosed mild-to-moderate hypertension or unresponsive or poor tolerability to earlier antihypertensive monotherapy. 40 After 12 weeks of treatment, the mean diastolic blood pressure reduction in the torasemide-pr group versus torasemide-ir met the noninferiority criterion. In addition, a significantly higher percentage of patients in the torasemide-pr group achieved adequate blood pressure control after 12 weeks. Ambulatory 24-h blood pressure monitoring in a subset of patients showed greater daytime systolic blood pressure reductions in the torasemide-pr group than in the torasemide-ir group. As the superiority of ambulatory blood pressure monitoring to casual blood pressure measurement in the prediction of cardiovascular risk and target organ damage is well established, it can be concluded that torasemide-pr provides a higher target organ protection than torasemide-ir. CONCLUSIONS Hypertensive heart disease is a common complication in hypertensive patients and is responsible for poor prognosis in this population. The histopathological substrate, myocardial remodeling, is the determinant factor of the complications present in patients with hypertensive heart disease, particularly diastolic dysfunction that progresses to diastolic HF (Figure 4). Given that CKD promotes myocardial remodeling from early stages, hypertensive patients with CKD are very prone to this cardiac disease and its complications. There is evidence that long-term treatment with different loop diuretics may have a variable impact on myocardial fibrosis in chronic HF patients. In fact, although torasemidetreated patients exhibited a reduction in myocardial collagen accumulation and a diminution of collagen type I synthesis, furosemide-treated patients did not. Further studies are required to definitively prove that torasemide, in particular S21

4 r e v i e w B López et al.: Myocardial fibrosis in chronic kidney disease CKD (+HTN) Hemodynamic and humoral alterations Myocardial molecular disturbances (> PCP activation) > Collagen synthesis Myocardial fibrosis Impairment of LV diastolic function Diastolic HF > Cardiac morbidity and mortality Figure 4 Mechanisms and consequences of the myocardial antifibrotic effects of torasemide. Proposed cardioprotection afforded by torasemide in patients with chronic kidney disease (CKD). HTN, hypertension; PCP, procollagen type I carboxy-terminal proteinase; LV, left ventricular; and HF, heart failure. its PR formulation, possesses cardioprotective properties, which in turn, may provide an additional benefit, beyond its renal actions in patients with CKD (Figure 4). DISCLOSURE Javier Diez has received consulting fees from Novartis and lecture fees from Merck. Javier Diez has also received grant support from Merck and Pfizer and has a patent for Use of a C-terminal fragment of Cardiotrophin-1 as a marker of Cardiotropin-1 in plasma, Methods for the treatment of cardiac disease associates to myocardial fibrosis and Use of truncated PPAR-gamma inhibitors for the treatment of renal failure in hypertensive patients. Arantxa Gonzalez has a patent for Use of a C-terminal fragment of Cardiotrophin-1 as a marker of Cardiotropin-1 in plasma and Methods for the treatment of cardiac disease associates to myocardial fibrosis. Begona Lopez has a patent for Use of a C-terminal fragment of Cardiotrophin-1 as a marker of Cardiotropin-1 in plasma and Methods for the treatment of cardiac disease associates to myocardial fibrosis. The remaining authors have declared no financial interests. ACKNOWLEDGMENTS Sources of funding: European Commission contract number LSHM-CT REFERENCES 1. Tyralla K, Amann K. Cardiovascular changes in renal failure. 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