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Cardiovascular Research 1997 34(3):439-444; doi:10.1016/S0008-6363(97)00073-4
© 1997 by European Society of Cardiology
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Copyright © 1997, European Society of Cardiology

Compensated cardiac hypertrophy: arrhythmogenicity and the new myocardial phenotype. I. Fibrosis

Patrick Assayagb, François Carréa, Brigitte Chevaliera, Claude Delcayrea, Pascale Mansiera and Bernard Swynghedauwa,*

aU127-INSERM, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475 Paris Cedex, France
bService de Cardiologie B, Hôpital Bichat, Paris, France

* Corresponding author. Tel.: +33 (1) 42858065; fax: +33 (1) 48742315.

Received 5 June 1996; accepted 20 February 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Biological determinants of...
 3 Mechanisms and factors...
 References
 
The high incidence of arrhythmias in compensated cardiac hypertrophy is related to two independently regulated components—fibrosis and the adaptational phenotypic changes in membrane proteins linked to cardiac hypertrophy, and fibrosis. During the regression of hypertensive cardiopathy in middle-aged spontaneously hypertensive rats, the roles of cardiac hypertrophy and fibrosis can be analysed separately, revealing that both correlate independently with arrhythmias. In an experimental model of myocardial infarction it is possible to prevent arrhythmias with propranolol at the same time as cardiac hypertrophy, despite ventricular fibrosis. Fibrosis would appear to create arrhythmias both by anatomical uncoupling and by a re-entry mechanism generated by the zig-zag propagation of the transverse waveform. Triggered activity and automaticity depend on the membrane phenotype of the cardiocyte. They also play an important role, which is aggravated by myocardial heterogeneity.

KEYWORDS Arrhythmias; Hypertrophy; Propranolol; Fibrosis; Heart failure


   1 Introduction
Top
 Abstract
 1 Introduction
2 Biological determinants of...
 3 Mechanisms and factors...
 References
 
1.1 Incidence of arrhythmias in cardiac hypertrophy
Sudden death, presumably related to severe arrhythmias, accounts for at least 50% of deaths among patients with heart failure. Interestingly, the high incidence of arrhythmias in heart failure is unrelated to coronary artery disease [1, 2]. Epidemiological surveys, such as the Framingham study [3], have shown a high incidence of generally benign arrhythmias in patients with left ventricular hypertrophy (LVH). In addition, asymptomatic arrhythmias are associated with a higher mortality rate in subjects with LVH. Again, coronary artery disease is not linked to an increased risk of arrhythmias [4]. These findings have been confirmed by clinical studies [5, 6] showing a high incidence of benign and sometimes severe arrhythmias associated with compensated cardiac hypertrophy (CCH) or mild heart failure.

It is controversial whether benign arrhythmias, such as ventricular premature beats, are predictive of severe arrhythmias, but the findings of the CAST trial argue strongly against this view [7]. In the meantime, several attempts have been made to predict severe arrhythmias by using various indexes. Heart rate variability (HRV), a recognised indicator of the autonomous nervous system (ANS) activity at the pacemaker level, is the oldest and most popular index. HRV is attenuated after a myocardial infarction and in both the failing heart and CCH, suggesting that the ANS activity disorders may also be causal [8]. More recently, quantification of the dispersion, duration, and variability of the QT interval was proposed as another prognostic factor together with the duration of the ventricular repolarisation phase [9].

Heart failure and myocardial infarction are known arrhythmogenic substrates associated with several predisposing factors, including metabolic and neurohumoral disorders, mechanical stretch due to acute ventricular dilation, ischemia, myocardial hypertrophy and fibrosis. ‘Contraction–excitation feedback’ was defined as the changes in the mechanical state that precede or alter the transmembrane potentials [10]. From a pathophysiologic point-of-view, ‘contraction–excitation feedback’ is a sort of pot-pourri comprising the direct effects of stretch and after-depolarisations, changes in action potential duration, increased dispersion of ventricular repolarisation and electrical instability. Whatever the definition, contraction–excitation feedback cannot be involved in CCH which have, by definition, a normal mechanical function.

In brief, the non-failing hypertrophied heart is a risk factor for potentially severe arrhythmias.

1.2 Potential biological substrate for arrhythmias
Our hypothesis is that arrhythmias in CCH are related to the new myocardial phenotype. By the new myocardial phenotype, we mean structural changes occurring in the myocardium during the onset of cardiac hypertrophy. Two independently regulated biological modifications—fibrosis and changes in membrane protein composition—play a determining role. These two biological factors are responsible for most of the other clinical manifestations of heart failure, including systolic and diastolic dysfunction [11]:

(i) Adaptation to mechanical stress includes several changes in the genetic expression of contractile and membrane proteins, and of proteins responsible for energy metabolism. Myocardial function is modified accordingly. The process has both benefits and limitations.

For example, slowing of the shortening velocity allows the heart to maintain a normal active tension in new environmental conditions, and improves economy at the tissue level [12]. It is also the first step in the reduction of cardiac output. The action potential duration and calcium transient are both prolonged contributing to the adaptational process, and facilitating arrhythmias (see below).

(ii) Fibrosis is unlikely to be a direct consequence of mechanical overload. It has multiple origins including ageing, ischemia, hormonal changes, inflammation and diabetes [13]. Fibrosis obviously has purely detrimental consequences on systolic and diastolic functions, and causes arrhythmias.

In summary, our working hypothesis is that the two biological determinants of arrhythmogenicity in CCH are changes in membrane proteins which participate in the adaptational process and increased collagen deposition.

This review will be restricted to acquired CCH, and thus excluding inherited cardiopathies. Part I attempts to decipher this complexity and the role of ventricular fibrosis. Part II will focus on the role of phenotypic modifications of the cardiocyte membrane proteins.


   2 Biological determinants of arrhythmias in CCH—a complex issue
Top
 Abstract
 1 Introduction
 2 Biological determinants of...
3 Mechanisms and factors...
 References
 
Ventricular fibrosis is fairly well-documented in CCH. The collagen volume fraction is increased in the hypertrophied left ventricle of patients with a previous history of arterial hypertension [13], and in several models of arterial hypertension without heart failure [14]. It is generally thought that fibrosis in hypertensive patients free of coronary artery disease results from the reduced coronary reserve due to arteriolar wall thickening [15]. It is our goal to bring together some experimental evidence that fibrosis is only one cause of arrhythmias.

Clinical investigations of arrhythmias in CCH are rare. In hypertensive cardiopathy, Gonzales-Fernandes [5] obtained a significant decrease in the prevalence and the severity of the ventricular ectopic activity by 6 months of treatment with angiotensin converting enzyme inhibitor (ACEI). Blood pressure and left ventricular mass were reduced by 18 and 35%, respectively. Both blood pressure and LVH correlate with the incidence of ventricular premature beats. Myocardial fibrosis was not quantified [4].

Pioneering work done by Marco Pahor [16] on an isolated heart preparation from 14-month-old spontaneously hypertensive rats (SHRs) showed a protective effect of ACEI after 11 months of treatment, in terms of both spontaneous arrhythmias and arrhythmias evoked by programmed electrostimulation. The degree of protection matched the fall in blood pressure (–16%) and the reduction in ventricular fibrosis (between –28 and –75%) and cardiac hypertrophy (–15%). The amount of replacement fibrosis was the best predictor of arrhythmias, but no attempt was made to study separately the role of cardiac hypertrophy and that of fibrosis in the genesis of arrhythmias.

2.1 Fibrosis is not the only determinant of ventricular arrhythmias in CCH
The quantitation of ventricular fibrosis necessitates serial biopsies or necropsy studies and has rarely been done in CCH [15]. The only available data are from animal experiments.

2.1.1 SHRs
We recently developed Holter monitoring of awake rats [17], and attempted to separate fibrosis from the other biological determinants of arrhythmias in 13- to 16-month SHRs, a well-documented model of CCH. Animals were selected and treated with an ACEI for 3 months at a dose which was slightly hypotensive and partly prevented cardiac hypertrophy. Arrhythmias and heart rate variability (HRV) were monitored by Holter recordings. Cardiac fibrosis was quantified morphologically.

Compared to age-matched Wistar rats, SHRs had more ventricular premature beats (VPB), bigger ventricles, more cardiac fibrosis and a slower heart rate (Table 1). ACEI treatment, as expected, prevented fibrosis and suppressed VPBs (Table 1). Routine statistical analysis of data on untreated and treated SHRs showed that the degree of cardiac hypertrophy (heart weight/body weight ratio) and the percentage of ventricular fibrosis (Table 1) were linked one another with a correlation coefficient of 0.77 (P<0.01). The number of VPBs per 24 h correlated both with cardiac weight and with collagen concentration.


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  		Table 1 Effects of an angiotensin converting enzyme inhibitor on systolic blood pressure, cardiac hypertrophy and ventricular fibrosis and influence on arrhythmias and Heart rate Variability, HRV, at rest (data are from [17], and unpublished data from this laboratory)

 
Principal component analysis using only 5 variables (heart weight, systolic blood pressure, supraventricular and ventricular premature beats, and collagen content) showed that untreated SHRs, treated SHRs and Wistar rats formed clearly distinct groups (Fig. 1A). Correspondence analysis (Fig. 1B) showed that the number of VPBs was proportional to the degree of fibrosis and cardiac hypertrophy only at the two extremes: i.e., when heart weight was normal or very high (HW1 and HW4 and Coll1 and Coll4 co-segregate with VPB1 and VPB4; Fig. 1B). In the intermediate situations, when cardiac hypertrophy was moderate, the incidence of VPBs was unrelated to the degree of cardiac hypertrophy or the collagen concentration (in Fig. 1B, HW2 co-segregates with VPB3, and HW3 and Coll3 co-segregates with VPB2). Such correlations strongly suggest that fibrosis and cardiac hypertrophy are independent arrhythmogenic factors.


Figure 1
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  		Fig. 1 Arrhythmias in middle-aged SHRs after angiotensin converting enzyme inhibition (reproduced from Chevalier et al. [17] with permission). Multivariate data analysis. (A) Cluster analysis. Two-dimensional projection of the multidimensional system including all the variables (see Chevalier et al. [17] for details). All rats, including treated and untreated Wistar rats and SHRs, were entered in the analysis (n=34). Axes 1 and 2 represent 53% of the total variance. The 4 experimental groups are represented by the limits of the graph. Parabola drawn corresponds to an intensity gradient of the discriminating modalities. (B) Correspondence analysis. Graphic representation obtained with the same parameters and experimental groups as in panel A. Five parameters are shown: HW = heart weight; Coll = collagen density; SBP = systolic blood pressure; SVPB and VPB = supraventricular and ventricular premature beats. Data are separated into 4 classes (5 for SVPB), for which upper and lower values are indicated in parentheses. Axes 1 and 2 represent 53% of the total variance.

 
The same tape records were also used to analyse HRV. The heart rate of rats is quite unstable relative to humans, making it difficult to use spectral analysis with Fourier transformation. We initially used a time domain method (the peak-and-trough method [18]) and were able to identify the same groups of oscillations in rats as in man, namely high- and low-frequency oscillations which have a vagal and both a vagal and sympathetic origin, respectively. To further analyse HRV in these middle-aged SHRs, we developed a time and frequency domain method of analysis known as ‘pseudo-smoothed Wigner-Ville transform’ [19]. The method is applicable to non-stationary signals, such as heart rate oscillations in small rodents, and shows the frequency pattern (in Hz) and the spectral power (in ms2) in 3D.

Heart rate is slower and HRV is attenuated in middle-aged SHRs as compared to age-matched Wistar rats with a significant reduction in the spectral power of low-frequency oscillations at rest. ACEI treatment normalises HRV and suppresses VPBs (Table 1). HRV is linked to blood pressure and cardiac hypertrophy, suggesting that the modifications of HRV are related to both myocardial structure and baroreflexes.

The conclusions of this study on an animal model of CCH were the following: (i) the main biological determinants of arrhythmias are both fibrosis and the phenotypic changes associated with cardiac hypertrophy; (ii) in contrast, the changes in HRV are unrelated to fibrosis, and mainly linked to cardiac hypertrophy, suggesting that the determinants of HRV are modifications of the myocardial phenotype such as the β-adrenergic/muscarinic receptor ratio (known to correlate with hypertrophy). This point will be developed in Part II.

2.1.2 Myocardial infarction in rats
An extensive experimental study by P. Belichard et al. [20] 5 weeks after coronary ligation in rats showed the role of ventricular remodelling in the inducibility of ventricular arrhythmias. Arrhythmias were induced under anaesthesia by programmed electrical stimulation in open-chest animals. The authors found the same reduction in the susceptibility to ventricular arrhythmias after treatment with ACEI or propranolol, although myocardial remodelling was extremely different in these two conditions. ACEI reduces cardiac hypertrophy, ventricular dilation and fibrosis in parallel. In contrast, propranolol does not modify the degree of cardiac hypertrophy, and even enhances both ventricular fibrosis and dilation. Propranolol therapy was stopped 48 h before the electrophysiological study to rule out any direct blocking effect of the drug. The unexpected conclusion was that in a pure model of reparative fibrosis + compensated hypertrophy, propranolol reduced the incidence of arrhythmias despite a detrimental effect in terms of fibrosis. It suggests that it "led to changes in sarcolemmal characteristics that reduce the risk of arrhythmias" [20].


   3 Mechanisms and factors known to predispose to arrhythmias
Top
 Abstract
 1 Introduction
 2 Biological determinants of...
 3 Mechanisms and factors...
References
 
Assuming that fibrosis is not the only determinant of arrhythmias, three basic mechanisms may be involved in the genesis of premature beats: re-entry, abnormal automaticity and triggered activity.

3.1 Re-entry
Re-entry is a mechanism of maintenance of arrhythmias and is directly linked to fibrosis. The propagated impulse may recycle (‘re-enter’) through an abnormal alternative pathway. In addition, re-entry requires a conduction block in the normal conductive pathway together with slowed conduction so that the conduction time in the re-entry circuit exceeds the refractory period of the conducting tissue. Fibrosis can create the alternative pathway and conduction block, and could slow conduction.

Fibrosis is one component of the ‘arrhythmogenic substrate’ [21] responsible for the genesis and maintenance of triggered ventricular arrhythmias after myocardial infarction. The topic has been extensively reviewed [21]. Ventricular tachycardia is rare in CCH, and the concept of an arrhythmogenic substrate cannot easily be applied to this condition, as shown by Pringle et al. in hypertensive patients [6]. In the senescent human heart Spach and Dolber [22] proposed an alternative explanation, called the ‘zig-zag mechanism’. The collagen fibre network of the senescent heart is very like that of the CCH. In young preparations, the advancing wave-front of depolarisation and the associated extracellular potential waveforms are smooth in every direction. In contrast, aged preparations show a prominent zig-zag course of transverse propagation which accounts for the increased complexity of the waveforms. The waveform differences correlate with the development of collagenous septa that fractionate myofibre bundles. The consequence is a decreased transverse conduction velocity which favours re-entry in cardiac muscle with normal electrophysiological properties. The re-arrangement of the collagen network in CCH [13, 14, 17] leads to the encircling of myofibres and then prevents side-to-side interactions and obliterates the existing intergroup couplings and the corresponding lateral impulse conduction.

The same mechanism has been proposed in patients with hypertrophied [23] (HCM) or dilated [24] (IDC) cardiomyopathies. Electrograms were recorded from 3 different right ventricular sites during pacing and intraventricular conduction curves were drawn showing an increased dispersion and inhomogeneity of conduction in patients with HCM who are at risk of sudden death [23]. Patients with IDC undergoing cardiac transplantation were examined with a similar technique, and the amount of fibrosis was again found to correlate with severely abnormal propagation [24].

3.2 Other mechanisms
Re-entry is unlikely to be the only mechanism responsible for arrhythmias. In a purely mechanical non-ischemic rabbit model of cardiac failure, it was shown that spontaneously occurring VPBs, couplets and episodes of ventricular tachycardia are due to non-re-entrant mechanisms arising in the subendocardium [25]. This conclusion was based upon the absence of electrical activity between the termination of the preceding beat and the initiation of the next, despite the presence of 232 intervening intramural recording sites per heart. This work suggests that arrhythmias originate from triggered activity or abnormal automaticity [25]. These electrophysiological mechanisms cannot be linked to fibrosis only. Delayed after-depolarisations and triggered activity have been found in a rat model of CCH due to renal hypertension [26].

Ischemia due to arteriolar wall thickening [15] may be one of the non-re-entrant mechanisms capable of initiating arrhythmias. It has also been proposed that the new myocardial phenotype favours automaticity and triggered activity.

Two different biological substrates may explain the increased automaticity of ventricular cells in CCH. A diminished capacity to restore a low resting calcium level during diastole, due to alterations in calcium handling by the sarcoplasmic reticulum (SR), could lead to an increased calcium concentration in the cytosol. In turn, this would create automaticity by triggering calcium release from the SR. A vicious cycle of premature contractile activity is then initiated [27]. The other mechanism involves the expression of ionic channels, such as If, which normally initiate slow depolarisation in the sinus node [28].

Abnormal activity can be triggered by impulse generation due to early or delayed after-depolarisation. Early afterdepolarisation is facilitated by the increased duration of action potentials, a well-known finding in CCH [29], and, in turn, may result from changes in the expression of various ionic channels genes. These two mechanisms will be analysed in greater detail in Part II.

The mechanisms of arrhythmias in CCH thus include re-entry, a direct consequence of fibrosis, triggered activity and abnormal automaticity which are both related to structural changes in membrane proteins. In addition, ventricular fibrosis causes anatomical uncoupling. The resulting myocardial heterogeneity will, in turn, enhance the propensity of the hypertrophied myocyte to develop triggered activity and automaticity.

Time for primary review 41 days.


   References
Top
 Abstract
 1 Introduction
 2 Biological determinants of...
 3 Mechanisms and factors...
 References
 

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