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NDT Advance Access originally published online on November 1, 2005
Nephrology Dialysis Transplantation 2006 21(1):20-23; doi:10.1093/ndt/gfi237
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Editorial Comment

Hypertensive myocardial fibrosis

Cesare Cuspidi1,2, Michele Ciulla1,2 and Alberto Zanchetti2,3

1 Istituto di Medicina Cardiovascolare, 2 Centro Interuniversitario di Fisiologia Clinica e Ipertensione, Universita’ di Milano, Ospedale Maggiore Policlinico, IRCCS and 3 Istituto Auxologico Italiano IRCCS, Milano, Italy

Correspondence and offprint requests to: C. Cuspidi, Centro Interuniversitario di Fisiologia Clinica e Ipertensione, via F. Sforza 35, 20122 Milano, Italy. Email: dhipertensione{at}libero.it

Keywords: fibrosis; hypertension; left ventricular hypertrophy



   Introduction
Top
 Introduction
Pathophysiology of cardiac...
 Diagnosis of myocardial fibrosis
 Regression of cardiac fibrosis
 Conclusions
 References
 
A variety of cardiac structural and functional changes, such as increased left ventricular mass (LVM), left atrial and aortic root enlargement, LV dysfunction, impairment of coronary reserve and prolonged ventricular repolarization, have been described in patients with long-standing arterial hypertension [1,2]. However, subtle modifications in LV structure and geometry may occur also in the early phases of the natural history of essential hypertension [3]. Among these manifestations of target organ damage, most attention has been devoted to LV hypertrophy (LVH), because the prevalence of this phenotype is relatively high and is associated with an increased risk of cardiovascular morbidity and mortality [4,5].



   Pathophysiology of cardiac fibrosis
Top
 Introduction
 Pathophysiology of cardiac...
Diagnosis of myocardial fibrosis
 Regression of cardiac fibrosis
 Conclusions
 References
 
Normal myocardium is composed of cardiac myocytes, tethered to an extracellular matrix of fibrillar collagen; they represent one-third of all cells, with cells other than cardiomyocytes accounting for the remaining two-thirds [6]. A large body of evidence indicates that myocardial structure in hypertensive LVH is affected by two key pathological processes: myocyte hypertrophy and a progressive accumulation of fibrous tissue within the cardiac interstitium [7–9]. Thus, in hypertensive LVH, a homogeneous tissue becomes heterogeneous, as a disproportionate accumulation of cells other than cardiomyocytes occurs, accounting for the development of alterations in myocardial texture. Both post-mortem and endomyocardial biopsy studies have shown that along with a variable increase in LVM, the collagen volume fraction (CVF) of the myocardium is increased in hypertensive patients compared with their normotensive counterparts; moreover, histologic evidence of fibrosis such as focal scars, endocardial or interstitial fibrosis has been found during the early phases of hypertension in patients with a mild degree of LVH [10–12].

Both haemodynamic and non-haemodynamic factors play a synergic role in myocardial fibrosis. Chronic pressure overload stimulates both procollagen gene expression and collagen protein synthesis leading to excessive collagen deposition and fibrosis. Two types of findings suggest that besides the pressure overload, other biological variables may contribute to myocardial fibrosis: (a) fibrosis has been found not only in the left ventricle but also in the right one in post-mortem studies of hypertensive individuals with LVH [13]; (b) the ability of different antihypertensive drugs to regress fibrosis in hypertensives with biopsy-proven myocardial fibrosis, is independent of their antihypertensive efficacy [14]. Myocardial fibrosis is a complex phenomenon reflecting the loss of the physiological reciprocal regulation between stimulatory (e.g. angiotensin II, endothelin I, catecholamines, aldosterone, basic fibroblast growth factor, insulin-like growth factor, etc.) and inhibitory factors (prostaglandins, nitric oxide, natriuretic peptides etc.) acting on the turnover of fibrillar collagen [15].

Several lines of evidence support a role for angiotensin II as a critical factor responsible for myocardial fibrosis. Angiotensin II induces fibroblast proliferation, alteration of fibrillar collagen turnover and stimulation of aldosterone, leading to accumulation of collagen type I and III fibres and fibrosis [16]. This accumulation results in a distortion of tissue structure, which is responsible for the increase in myocardial stiffness leading to diastolic dysfunction, a substrate for ventricular arrhythmias, and ultimately to systolic dysfunction [17].



   Diagnosis of myocardial fibrosis
Top
 Introduction
 Pathophysiology of cardiac...
 Diagnosis of myocardial fibrosis
Regression of cardiac fibrosis
 Conclusions
 References
 
Cardiac biopsy is certainly the gold standard in this regard, but for obvious reasons endomyocardial biopsies for antemortem measurements of the myocardial collagen volume fraction (CVF) have been limited to a small number of patients. The possibility that cardiac fibrosis can be reliably detected and monitored over time by non-invasive techniques is supported by a growing body of evidence in this field. Different methodologic approaches such as biochemical markers of collagen synthesis and degradation, cardiac hormones and ultrasonographic procedures have been developed and validated against CVF as measured in endomyocardial biopsies.

Serum markers of collagen turnover can be classified according to their specific action: (1) markers of collagen synthesis [carboxy-terminal propeptide of procollagen type I (PIP), carboxy-terminal propeptide of procollagen type III (PIIIP)]; (2) markers of collagen degradation [carboxy-terminal telopeptide of collagen type I (CITP)]; (3) markers of collagen degradation inhibition [tissue inhibitor of matrix metalloproteinases type I (TIMP I)]; (4) markers of fibroblast activity [transforming growth factor ß1 (TGF ß1)]. Serum markers of collagen synthesis or degradation have been investigated and found to be altered in hypertension [18]. In particular, numerous studies have shown that serum PIP was significantly higher in hypertensives with LVH than in normotensive controls [19–21]. It correlated with CVF on endomyocardial biopsies [19] and decreased in parallel with its regression during antihypertensive treatment [22]. Furthermore, a marked increase in TIMP I was found in hypertensive patients with echocardiographic evidence of diastolic dysfunction compared with patients with normal LV diastolic filling and to normal subjects [23].

Collagen deposition increases acoustic impedance markedly. The impedance of fibrotic tissue is about 10 000 times higher than that of surrounding tissues. The presence of fibrosis has a definite impact on the echo texture image of myocardium. Therefore, characterization of the composition of heart tissue using specific ultrasound technology, an extension of conventional echocardiography, is a promising application for detection of fibrosis and evaluation of myocardial physical properties, [24]. Current echocardiographic procedures for assessing myocardial fibrosis comprise backscatter analysis of returning echoes and quantitative echoreflectivity analysis. Backscatter analysis provides a measurement of morphological and functional properties of myocardium by evaluating the cyclic variations in returning ultrasound signal intensity (cyclic variation in backscatter); with this approach several investigators have shown a good correlation between integrated backscatter signal intensity and CFV in diverse cardiac disorders including moderate and severe hypertensive LVH [25,26]. The echoreflectivity method (or videodensitometry) analyses the gray scale of individual pixels obtained from specific regions inside the ultrasonic image; specific image analysis softwares providing a detailed frequency histogram of reflected echo amplitudes are used for this purpose. Echoreflectivity studies in humans have demonstrated a direct close relation between indices of echo amplitude and CVF in both hypertensive and non-hypertensive heart disease [12]. Despite the recognized value of ultrasonographic methods in detection of myocardial fibrosis, their application in clinical practice has been limited by the difficulties in setting up a system for a reliable tissue characterization.



   Regression of cardiac fibrosis
Top
 Introduction
 Pathophysiology of cardiac...
 Diagnosis of myocardial fibrosis
 Regression of cardiac fibrosis
Conclusions
 References
 
Although it has been proven that antihypertensive therapy can reverse or substantially reduce LVH, limited information is available about the effects of treatment on various myocardial tissue compartments. For the reversal of myocardial fibrosis, drugs are necessary which reverse the deranged balance between stimulatory and inhibitory signals impacting on collagen turnover. To date, both experimental and human studies have investigated this possibility in an effort to answer two unsolved questions:

  • Is LVM reduction always associated with regression of myocardial fibrosis ?
  • Are antihypertensive drugs equally effective in reducing myocardial fibrosis ?

In a seminal study, designed to distinguish the relative importance of different antihypertensive drugs in the regression of myocardial fibrosis of rats with renovascular hypertension and LVH, equipotent doses of zofenopril, nifedipine and labetalol normalized BP and LVM, while only zofenopril and labetalol were found to regress myocardial fibrosis [14]. The findings of this study indicate that not all antihypertensive agents have antifibrotic effects and cardiovascular tissue specificity. Regression of myocardial fibrosis has been proven also in man by a limited number of studies performed in a small series of patients with myocardial fibrosis assessed by cardiac biopsy. In a double blind randomized trial, 35 hypertensive patients were randomized to receive either the ACE-inhibitor lisinopril or hydrochlorothiazide, in addition to their preexisting antihypertensive regimen [27]. Only individuals randomized to lisinopril had a regression in fibrosis associated with an improvement of diastolic function. Further evidence on selective cardiac fibrosis regression refers to larger studies using non-invasive biochemical and ultrasonographic markers. In the LVH Regression with the Angiotensin Antagonist Losartan (REGAAL) study including 225 patients, losartan numerically reduced LVMI more than atenolol and, at variance from atenolol, significantly decreased the concentration of both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) [28]. These neurohormones are considered as tissue markers for LVH and fibrosis and their reduction may be a more sensitive index of LVH regression than LVMI. More recently, an echoreflectivity study was performed in a subgroup of 106 patients of the REGAAL cohort. Using adequate echocardiographic scans to evaluate the cardiac texture evaluation, the investigators found that the prevalence of excessive fibrosis (defined as broad band >100 colour levels) was unchanged by atenolol but decreased by losartan [29]. The reduction in fibrosis with losartan, clearly documented in this analysis, may have contributed to the protective action of losartan documented in the LIFE study [30].



   Conclusions
Top
 Introduction
 Pathophysiology of cardiac...
 Diagnosis of myocardial fibrosis
 Regression of cardiac fibrosis
 Conclusions
References
 
Myocardial fibrosis is a key pathological process in LVH. It is the result of chronic arterial hypertension and contributes to abnormalities of cardiac function, of coronary reserve and of electrical activity. These abnormalities adversely affect the clinical outcome of hypertensive patients. This means that not only the quantity, but also the quality of cardiac tissue is responsible for cardiovascular events in patients with hypertensive LVH. The optimal treatment of hypertensive patients should target a parallel decrease in cardiac mass and fibrosis. Preliminary evidence suggests that not all antihypertensive agents affect fibrosis to the same extent. Agents directly blocking the renin–angiotensin system (ACE-inhibitors and ARBs) appear particularly effective, in contrast to betablockers and diuretics. Finally, it remains to be investigated whether fibrosis and its regression correlate equally, or even better, than mass and its regression with subsequent cardiovascular events.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Pathophysiology of cardiac...
 Diagnosis of myocardial fibrosis
 Regression of cardiac fibrosis
 Conclusions
 References
 

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Received for publication: 21. 9.05
Accepted in revised form: 3.10.05


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