PHYSIOLOGICAL REVIEWS   Vol. 79 No. 1 January 1999, pp. 215-262
Copyright ©1999 by the American Physiological Society

Molecular Mechanisms of Myocardial Remodeling

BERNARD SWYNGHEDAUW

Institut National de la Santé et de la Recherche Médicale U. 127, Hôpital Lariboisière, Paris, France

I. DEFINITION: LIMITATIONS
II. MORPHOLOGICAL AND CLINICAL BASIS
    A. Anatomic Basis
    B. Cellular Alterations
    C. Clinical Setting and Treatment
III. PHENOTYPIC CHANGES IN MYOCYTES
    A. Methodological Problems
    B. General Process of Biological Adaptation
    C. Cardiac Hypertrophy
    D. Energy Metabolism
    E. Membrane Proteins
    F. Contractile Proteins
    G. Contractile Cycle and Excitation-Contraction Coupling
    H. Cardiac Autocrine Functions
    I. Cytoskeleton
IV. PHENOTYPIC CHANGES IN THE EXTRACELLULAR MATRIX
    A. Normal Cardiac Extracellular Matrix
    B. Myocardial Fibrosis of Known Origin
    C. Cardiac Overload Without Fibrosis
    D. Pressure Overload Hypertrophy
    E. Other Components of Fibrosis
    F. Other Components of the Extracellular Matrix
V. CELL DEATH
    A. Ischemia
    B. Cardiac Hypertrophy and Failure
    C. Vasoactive Peptides and Catecholamines
VI. CHANGES IN GENE EXPRESSION IN RELATION TO MYOCARDIAL FUNCTION
    A. Systolic Ejection and Active Relaxation
    B. Diastolic Dysfunction
    C. Arrhythmias and Changes in Heart Rate
    D. Transition to Cardiac Failure
VII. CARDIAC REMODELING DUE TO SENESCENCE
    A. The Senescent Heart: an Overloaded Heart
    B. Senescence of the Myocardium: a Specific Biological Process
VIII. CONCLUSION
REFERENCES

	ABSTRACT

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Swynghedauw, Bernard. Molecular Mechanisms of Myocardial Remodeling. Physiol. Rev. 79: 215-262, 1999.  "Remodeling" implies changes that result in rearrangement of normally existing structures. This review focuses only on permanent modifications in relation to clinical dysfunction in cardiac remodeling (CR) secondary to myocardial infarction (MI) and/or arterial hypertension and includes a special section on the senescent heart, since CR is mainly a disease of the elderly. From a biological point of view, CR is determined by 1 ) the general process of adaptation which allows both the myocyte and the collagen network to adapt to new working conditions; 2) ventricular fibrosis, i.e., increased collagen concentration, which is multifactorial and caused by senescence, ischemia, various hormones, and/or inflammatory processes; 3) cell death, a parameter linked to fibrosis, which is usually due to necrosis and apoptosis and occurs in nearly all models of CR. The process of adaptation is associated with various changes in genetic expression, including a general activation that causes hypertrophy, isogenic shifts which result in the appearance of a slow isomyosin, and a new Na⁺-K⁺-ATPase with a low affinity for sodium, reactivation of genes encoding for atrial natriuretic fator and the renin-angiotensin system, and a diminished concentration of sarcoplasmic reticulum Ca²⁺-ATPase, -adrenergic receptors, and the potassium channel responsible for transient outward current. From a clinical point of view, fibrosis is for the moment a major marker for cardiac failure and a crucial determinant of myocardial heterogeneity, increasing diastolic stiffness, and the propensity for reentry arrhythmias. In addition, systolic dysfunction is facilitated by slowing of the calcium transient and the downregulation of the entire adrenergic system. Modifications of intracellular calcium movements are the main determinants of the triggered activity and automaticity that cause arrhythmias and alterations in relaxation.

	I. DEFINITION: LIMITATIONS

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"Remodeling" qualifies changes that result in the rearrangement of normally existing structures. Although remodeling does not necessarily define a pathological condition, myocardial remodeling is usually restricted to diseased conditions. The above definition eliminates gestational and developmental aspects and also the so-called physiological cardiac hypertrophy that follows intensive exercising.

Although "myocardial remodeling" is now a widely used term, from a historical point of view it was initially used to describe the remodeling that occurs following myocardial infarction (MI). The meaning of the word was subsequently extended and used to qualify a variety of conditions including pure mechanical overload as well as hypertensive, valvular cardiopathy, familial hypertrophic, and dilated cardiomyopathy (reviewed in Ref. 410; see Table 1). Transgenic manipulations (reviewed in Ref. 446) as well as experimental or clinical hormonal intoxications (due to thyroxine, angiotensin II, aldosterone) are also able to remodel the myocardium. In general, myocardial remodeling is a reversible process provided the cause of the remodeling has been either suppressed or attenuated. This has considerable links to clinical and basic pharmacology and has been extensively reviewed recently (432).

The literature on the subject is extensive, and the present review is focused on permanent modifications in the left ventricle in relation to clinical dysfunction, in the most commonly observed conditions of CR, i.e., myocardial ischemia and/or arterial hypertension. Hibernating myocardium is a reversible state of persistently impaired ventricular function at rest which copes with a reduced coronary blood flow. The hibernating response may be acute or chronic and could be considered to be a process of adaptation. The biological mechanisms of hibernation need a specific approach and are excluded from the present review. From an epidemiological point of view, MI and arterial hypertension are both more frequent in aged persons. In addition, the structural modifications that are observed during senescence in healthy individuals has several points in common with the mechanically overloaded heart (32).

Cardiac remodeling is triggered by mechanical stretch; nevertheless, there are also several different factors including ischemia, hormones, and vasoactive peptides, which can modify the effects of the mechanical factor. The most common clinical situation during which remodeling is known to occur is a rather complex mixture of ischemia, stretch due to pressure overload, stress due a myocardial scar, and increased plasma levels of hormones or vasoactive peptides. An additional factor has to be listed, namely, the unknown signal that provides to the heart the information concerning the amount of substance that has been lost after MI and that is exactly recovered by the compensatory hypertrophy; such a signal should be similar to that occurring after uninephrectomy, unipneumonectomy, or partial hepatectomy. The mechanisms by which cardiac growth occurs have already been reviewed (85, 108, 234, 346, 515), and because they could themselves constitute a full review, they are not developed in this review.

The permanent changes in molecular structure and their consequences in terms of cell physiology can be divided into three principal mechanisms: the deleterious consequences of the general process of adaptation, including cardiac hypertrophy, cell death, and fibrosis. The goal of this review is not only to review the extensive literature concerning CR, but also to try to simplify a complex problem and to identify pathways for future research. A review on the same topic was published in 1982 (449); only a selection of the articles published before this date have been quoted.

	II. MORPHOLOGICAL AND CLINICAL BASIS

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Cardiac remodeling is accompanied by an increase in LV mass and volume and a change in the shape of the ventricle (89, 90). If the process is triggered by MI, the remodeling is asymmetric and is associated with infarct expansion.

Early ventricular remodeling following coronary occlusion is dominated by infarct expansion, which is an acute dilation of the infarction area that cannot be explained by additional myocardial necrosis. Infarct expansion is caused by death and slippage of the myocytes; it usually predominates in the apical region of the left ventricle and dramatically alters ventricular volume and geometry. In rats, two days after a MI causing a loss of 63% of the myocytes, the transverse mid chamber diameter increases by 20% and the wall thickness decreases by 33%. Simultaneously, both the total number of myocytes and capillary profile in the spared region of the LV free wall are reduced by 40%. The combination of these abnormalities indicates side-to-side myocyte slippage and accounts for the seven- to eightfold increase in diastolic wall stress (338).

Ventricular remodeling is the result of infarct expansion of akinetic-dyskinetic segments and volume-overload hypertrophy of noninfarcted segments. Catheterization and ventriculography have demonstrated a volume enlargement, a lengthening of the ventricular perimeters, and an increased sphericity index both in systole and diastole that is accompanied by a blunting of the normal curvature of the apex. Later, what is usually called remodeling is characterized by additional enlargement and sphericity of the ventricle, a decrease in stroke volume, and impaired diastolic filling (88, 148, 208, 288, 303, 352). Based on these observations, the following model of ventricular remodeling after MI has been proposed: systolic impairment secondary to the loss of contractile material results in an increased end-systolic volume, an increased cardiac size, and a secondary augmentation of the diastolic filling pressure and distensibility. As the fibrosis increases, the distensibility decreases, resulting in an increase in diastolic pressure and volume. Peripheral mechanisms including vasoconstriction subsequently increase both preload and afterload, which results in an increased wall stress and a progressive thinning of the area. Simultaneously, in noninfarcted segments, elevation of the end-diastolic stress causes volume-overload hypertrophy that tends to normalize the wall stress according to Laplace's law. The extent and location of the infarction, therapy, or associated diseases may considerably modify remodeling (288).

When CR originates from a more general process such as arterial hypertension or valvular disease, the ventricular hypertrophy remains symmetric. Compensated cardiac hypertrophy (CCH) is concentric and is initially characterized by a thick ventricular wall and septum, a normal internal volume and wall stress, and a high mass-to-volume ratio. Cardiac failure (CF) is progressive and is accompanied by a progressive enlargement of the ventricular cavity, and the mass-to-volume ratio returns to normal values (444).

The first demonstration that, in adults, cardiac myocytes hypertrophy and cardiac nonmuscular cells both hypertrophy and divide by mitosis was made using thymidine labeling in the laboratory of Rabinowitz and co-workers (163, 319). This finding provided the basis for the general belief that postnatal growth of cardiocytes occurs through myocyte hypertrophy and that cardiac myocytes are terminally differentiated cells that are unable to reenter the cell cycle. In contrast, in the nonmuscle cells, which include both fibroblasts and endothelial cells, a hyperplastic component persists. Therefore, CR is a result of myocyte hypertrophy, hyperplasia, and hypertrophy of the nonmuscular cells and interstitial cell growth. Such a paradigm has however to be reevaluated, since CR is also known to be associated with polyploidy (this has been well documented in the hypertrophied human heart; Refs. 2, 487), myocyte loss (see sect. V ), myocardial damage, and probably DNA repair. In addition, there is evidence based on quantitative morphometry that, at least in human hearts (but it is nearly impossible to experimentally obtained very bulky hearts, discussed in Ref. 187), severe degrees of cardiac hypertrophy are accompanied by cardiocyte proliferation (21, 258). There are also convincing data showing mitotic images in atrial and ventricular cardiocytes during CF in humans and in the region adjacent to the necrotic area in both human hearts and in experimental models of MI (363, 384). With the use of a morphometric approach, the mitotic index for cardiocyte nuclei was rather high in the end-stage failing hearts compared with fetal hearts and was increased in the surviving tissue bordering the acute infarction. However, mitotic images observed during CF may not necessarily be indicative of cell division but could be a prerequisite for polyploidy, multinucleation, DNA repair, and even DNA fragmentation and cell death (363). Compensated cardiac hypertrophy is essentially caused by myocyte hypertrophy and hyperplasia of the nonmuscle cells; nevertheless, adult cardiocytes may not all be terminally differentiated cells, and mitotic divisions of the myocytes may constitute a growth reserve for severely damaged myocardium.

Cardiocyte hypertrophy is the result of a sarcomeric reorganization. Dilation of the heart is associated with myocyte lengthening, which is mediated by the generation of new sarcomeres in series resulting in a pronounced enhancement of the length-to-width ratio of the myocytes. The same phenomenon is observed in the rat 2 or 6 days after birth. This would suggest that during CF a fetal gene program involving activation of the cytoskeletal proteins is initiated that regulates the overall shape of the myocyte by preferentially directing lengthening of the cell. In contrast, hypertrophy of cardiomyocytes is the result of the addition of new sarcomeres in parallel (152). Such a hypothesis is favored by the observation made by Samuel and co-workers (393, 394) showing a reversible rearrangement of the microtubular network during the early stage of cardiac overload.

Cardiac remodeling after MI is accompanied by a progressive decline in ejection fraction over time, which suggests that CR, in this condition, would be better quantitated by measuring the LV ejection fraction (89, 148). In hypertensive cardiopathy, there is a consistent and graded relation between blood pressure and the degree of concentric ventricular hypertrophy. Systolic and diastolic dysfunction is progressive and is correlated with ventricular dilation.

Several groups of clinical trials, using vasoactive drugs (89), -adrenergic blocking agents (123), converting enzyme inhibitors (CEI) (93, 430), or spironolactone (522) have provided evidence that structural remodeling can be not only attenuated but even reversed and that the treatment of CR and its adverse effects can be targeted solely to the biological function of the myocardium.

Recent clinical trials have demonstrated the existence of two groups of vasoactive drugs: ₁ -blockers, such as prazosin, which have no effect either on mortality rate or ejection fraction, and drugs such as hydralazine, isorbide dinitrate, and CEI that improve both the mortality rate and the ejection fraction. The first category of drugs has no effect on the progressive development of cardiac hypertrophy and dilation. In contrast, CEI significantly reduces LV mass and volume (90). Therefore, it is now possible to treat CR. In addition, such trials show that vasoactive peptides, like angiotensin II, have both a hemodynamic and a trophic effect.

The effects of -adrenergic blockade with bucindolol or carvedilol have also been examined in several placebo-controlled studies involving patients with CF and systolic dysfunction due to profound CR (123). In all studies, LV ejection fraction was consistently improved and ventricular volume reduced. These effects appeared after 3-6 mo of continuous therapy. Such a long-term treatment also reverses CR by decreasing ventricular mass and volume. There was also an increase in the sphericity index, which indicates that the ventricle recovers its ellipticity.

	III. PHENOTYPIC CHANGES IN MYOCYTES

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Because of the development in molecular and cellular biology, we have learned that, in response to mechanical stimuli, both the myocardium and the vascular walls adapt to increased work loads by changes in gene expression. However, nature has not provided infinite possibilities of new genetic programs. If one looks back during development, such programs are usually available. In other words, to know, in a given animal species, what the genetic programs could be reexpressed in a given condition, the best strategy consists of exploring simultaneously the pattern of gene expression during development and in the pathological state. Such a strategy has been successfully applied to mechanical overload and has led to the discovery that, during mechanical overload, only fetal isoforms were reexpressed in this condition (Table 2). In skeletal muscle, hypertrophy due to intensive training or during muscle regeneration is accompanied by the reexpression of several programs, including a fetal and an embryonic program because there are two programs that are expressed during development (442).

Nevertheless, in terms of genetic expression, there are differences between an embryo and patient suffering from arterial hypertension. In the first case, the changes in genetic expression are part of a sequential program. In the second case, the endogenous program is associated with several other programs resulting from complex and variable interactions between hormones, neurotransmitters, and plasma peptides. It is one of the goals of this review to try to separate these two components from each other.

Molecular or cellular studies on CR have raised several specific problems. 1 ) There are several experimental models of cardiac hypertrophy available, such as Goldblatt, aortic insufficiency, or abdominal aortic stenosis that need experienced hands to provide reproducible results and a reasonable (>35%) degree of cardiac hypertrophy (187). Several outstanding biochemical or biological studies have indeed been based on experimental models that gave rise to a cardiac hypertrophy of 20% or less (421). Experimental models of CF are rare, expensive [i.e., aging spontaneously hypertensive rats (SHR); Ref. 47], and sometimes far away from the clinical reality, for example, the tachycardia-induced model which is not accompanied by hypertrophy (523). 2) The world-wide initiation of active cardiac transplantation programs has provided the possibility to obtain human tissue samples from both control and end-stage failing hearts [New York Heart Association (NYHA) stage IV], including ischemic cardiopathy and idiopathic cardiomyopathy, for physiological, molecular biological, and enzymatic use. Control samples can be obtained from donor hearts which proved to be unsuitable for transplantation or from tissue discarded during surgical procedures. End-stage failing hearts always come from patients with end-stage disease, and it is therefore frequently difficult to decide whether the differences reported between experimental animal models and human material are due to species differences or reflect real different stages of the disease. 3) Technical and methodological problems are particularly frequent in this domain; extensive purification procedures may lead to selective extraction (see below a good example concerning the calcium-regulating proteins). For unknown reasons, highly reputed journals accept results based on small series of three to four patients, and even worse accept the utilization of a Student's t-test in such condition (some good examples are given in Tables 5 and 7). 4 ) In any model, including the human heart, the biological results cannot be interpreted without knowing two parameters: the stage of the disease, which is usually rather well documented, and the concentration of the major plasma hormones and peptides. Despite their major importance, the latter have unfortunately been rarely documented (142).

Species specificity is another crucial methodological problem. The molecular determinants of ventricular adaptation and dysfunction are indeed species specific (451). In contrast, an important conclusion of the previous thermodynamic study is that the fundamental physiological process of adaptation is the same, both in rabbits and humans (7). The causes of cardiac hypertrophy may differ from one animal species to another (for example, rats are resistant to atherosclerosis, dogs have a very particular valvular pathology, and CF in humans in the affluent western countries is mostly secondary to hypertension and/or coronary insufficiency). Nevertheless, the most important cause of such a species specificity is the fact that ventricular contraction is regulated by different processes that depend on both the type and the size of the animal. There are species such as rats or rabbits in which the adaptational process is caused by modifications of both the contractile machinery and the calcium-regulating systems (129). In contrast, in humans (at least human ventricle) and guinea pigs, the contractile proteins are unlikely to be modified. The hypothesis is that in the latter group membrane proteins responsible for the calcium movements play a major role in the adaptational process (306, 481).

By comparing the results of mechanical studies performed on isolated fresh papillary muscles with those made on isolated skinned muscle fibers (fibers without any membrane structure) from pressure overloaded rats or guinea pigs (481), one can identify two different processes. When maximum shortening velocity (V_max ) is determined on fresh muscles, it is altered in both animals. In contrast, when muscular contraction is performed on skinned fibers, the shortening velocity is reduced only in pressure-overloaded rat hearts, but not in guinea pigs. This indicates that in the absence of membrane structures, the fundamental process of adaptation is still present in the rat, whereas it has disappeared in guinea pigs. Calculations based on heat production have indicated that in the rabbit ventricle the two mechanisms, namely, the sliding process and calcium movements, play roughly equivalent roles in the improvement of the economy (Fig. 1) (6). Molecular investigations have confirmed such a view, and with the comparison of the ventricles and atria, it has been shown that there is, in addition, a tissue specificity.

View larger version (15K): [in this window] [in a new window]   FIG. 1.   Energy transduction in cardiac remodeling. Data are expressed as percent controls. CCH, compensated cardiac hypertrophy due to pulmonary artery stenosis; HF, heart failure due to dilated cardiomyopathy in humans. Force-time integral is measured in isometric conditions. Shortening velocity is calculated in isotonic conditions. ** Significantly different from controls. [Data recalculated from Alpert et al. (7) and Hasenfuss et al. (183).]

Biological adaptation is a general process by which an organ or organism expresses a new genetic program in response to environmental changes that unbalance its thermodynamic status. The expression of such a program has to result in an improved thermodynamic state, which is referred to as adaptive. Mechanical overload of a striated muscle immediately reduces the instantaneous shortening velocity by simply bringing into play the mechanical properties of the myofiber. When the load is greater, the fiber contracts more slowly, and this results in an immediate decrease in the economy (i.e., the number of ATP molecules burned per gram of tension) of the system, since the muscle fiber has adapted to have an optimal economy for a given velocity (153, 158, 435).

The adaptational process is dominated by several changes in genetic expression that allow the heart to recover a normal economy. Quantitative modifications lead to cardiac hypertrophy and, according to Laplace's law, will normalize the wall stress. Simultaneously qualitative changes will allow the myocardial fiber to contract more slowly and to recover a normal economy by having a lower V_max and by using a different force-velocity curve (7, 246, 247). This phenomenon proceeds by trial and error, and the permanent changes in genetic expression simultaneously have, even at the beginning, both beneficial effects in terms of muscular economy and detrimental, or even useless, effects (383). Cardiac failure, when it occurs, indicates the limits of the process of biological adaptation (448).

The phenotypic changes (also called phenoconversion) are very similar in a variety of conditions, including fetal development, volume and pressure overload, senescence, or hypothyroidism. This coincidence is not fortuitous, since in each of these conditions the change in genetic expression is due to an external event, and the same program is always used simply because this is the only developmental program available (266).

Following the pioneer studies by Schreiber et al. (406) performed on isolated working guinea pig hearts, a considerable amount of work using radioactive amino acid labeling was performed, and extensive reviews have been published (311, 313, 443, 449). In brief, the activation of protein synthesis is a rapid and rather homogeneous phenomenon. Schreiber et al. (406) showed that total protein synthesis, including myosin, but not myoglobin, and collagen, were activated after 3 h of increased aortic pressure. Hatt et al. (189) were able to demonstrate polysomes in the myocardium 30 min after an acute overload. Following the imposition of a pressure overload, such as aortic stenosis, radioactive labeling of total proteins or myosin remained unchanged for 1 or 2 days, peaked at 5-6 days, and returned to control values within 2-3 wk (304, 370, 527). The accumulation of total proteins or myosin is due to an increased rate of synthesis; nevertheless, the rate of degradation is augmented in parallel, such a paradoxical wasting effect is a general feature in protein metabolism (304, 313). Molecular biological techniques using global approaches such as hybridization curves to evaluate mRNA complexity were unable to detect major differences between normal and hypertrophied hearts (26, 450). Different results were subsequently obtained using more sophisticated techniques such as differential display and specific hybridization procedures and are described in section VIII.

View larger version (18K): [in this window] [in a new window]   FIG. 2.   Myocardial calcium-regulating proteins in cardiac remodeling. Diagrammatic representation of cardiac myocyte internal and external membranes. Compensated cardiac hypertrophy, mainly experimental models; cardiac failure, mainly end-stage cardiac failure in humans; , increased activity (as compared with controls); , decreased activity; =, activity unchanged; SR, sarcoplasmic reticulum; SL, sarcolemma; Gs, -subunit isoforms of G transduction protein; 1- and 2-AR, 1- and 2-adrenergic receptors; M2R, muscarinic receptor.

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1. Isomyosin shift to V3

The myosin molecule is composed of a pair of myosin heavy chains (MHC) and two different pairs of myosin light chains (MLC), MLC1 and MPLC2. In the rat heart, there are three isomyosins: V1, V2, and V3, all of which possess the same pairs of MLC, MLC1v, and MPLC2v, but which differ by their MHC composition, in V1, in V2, and in V3. The fast skeletal myosin is composed of a different pair of MHC and MLC molecules, but the slow skeletal isomyosin is very similar to V3, since it is composed of the same MHC molecules, , and MLC1 molecule, MlC1v (also termed MlC1s), but differs from V3 by a specific MPLC2 molecule. The myosin ATPase-active site is located on the MHC head and depends on the structure of these subunits, the -isoMHC has the highest ATPase activity, whereas the -one possesses a low enzymatic activity. In phylogeny, when different muscles from various species are compared, a good correlation has been found between myosin ATPase, i.e., the type of MHC isoform, including "superactivated" ATPase (

View larger version (9K): [in this window] [in a new window]   FIG. 3.   Influence of stimulation frequency on isometric twitch tension, intracellular calcium transient (peak aequorin light), and action potential duration to 50 and 90% repolarization (APD50 and APD90, respectively) in strips from human nonfailing and end-stage failing myocardium. DCM, dilated cardiomyopathy. [From Pieske et al. (353), with permission. Copyright 1995 American Heart Association.]

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View larger version (13K): [in this window] [in a new window]   FIG. 4.   Defective excitation-contraction coupling in compensated cardiac hypertrophy. Illustrated is the fact that sarcolemmal calcium current activates calcium release from SR less efficiently in hypertrophied cells than in control cells. Whole cell current was quantitated by patch clamp. Calcium release from SR was directly assessed by measuring calcium sparks using a confocal microscope. A: control cells, Dahl salt-resistant rats. Depolarizing steps to 20 and +20 mV (top) activate calcium current (ICa ) (2nd panel), reflected as a running integral  ICa (3rd panel), triggering calcium sparks with a running integral of calcium occurrence (bottom). B: compensated cardiac hypertrophy, Dahl salt-sensitive rats, displayed as in A. C: voltage dependence of  Ps (obtained by integrating probability of evoking calcium sparks over a fixed time period) over 200-ms depolarization in control () and hypertrophied cells (). This curve indicated that there is less calcium release for a given voltage on hypertrophy than in control. D: voltage dependence of f"(i) [ratio of 2 previously described time intervals  ICa and  Ps, in (sparks/mm)/(pC/pF)] over 200 ms for control and hypertrophied cells. In hypertrophy, for a given voltage, there are less sparks produced by same amount of calcium current. E: [3H]ryanodine saturation curves in sarcoplasmic reticulum vesicles. Control and hypertrophied hearts had same dissociation constant and maximum binding. [From Gomez et al. (353), with permission. Copyright 1997 American Association for Advancement of Science.]

There are many lines of evidence which suggest that there is an early and rapid reorganization of the microtubular network and an activation of the expression of genes encoding several cytoskeletal proteins. The first suggestion that the microtubules may be involved in the cellular rearrangement at the onset of cardiac hypertrophy was made by Samuel and co-workers (393, 394) who showed a transient increase in the microtubular network of cardiocytes 2-4 days after aortic stenosis. It was suggested that the microtubules may play the role of a guideline in the phenotypic modifications affecting these cells. -Actin is also a cytoskeletal protein that plays an important role in the arrangement of microfilaments during myoblast growth. Western blot analysis revealed a similar and early transient increase in -actin in two models of cardiac hypertrophy, i.e., after transmyocardial direct-current shock or mitral regurgitation (70).

Permanent changes in the microtubules were reported more recently. Both the microtubular network and tubulin concentration were increased in overloaded cat ventricles 2 and 6 wk as well as 6 mo after pulmonary arterial stenosis. In contrast, volume overload showed no changes. This has been associated with a pronounced contractile deficit. Colchicine exposure or exposure to a temperature of 0°C depolymerizes the microtubular network, and in parallel normalizes the contractile dysfunction. In contrast, in control cells, a 2-h exposure to taxol, known to induce the polymerization process and to inhibit depolymerization, mimics the effects of a stress load and depresses the contractile function. It has been proposed that the microtubule network of the cytoskeleton imposes a resistive intracellular load on sarcomere shortening and, when in excess, impedes sarcomere motion (472).

Tagawa et al. (455), from the same laboratory, succeeded in measuring directly the extramyofibrillar cell stiffness and viscosity using magnetic twisting cytometry on isolated cardiocytes whose cell surface integrin receptors have been decorated with a synthetic peptide coated with ferromagnetic beads. These authors showed that the increased amount and polymerization of tubulin in right ventricular hypertrophy in the cat has major functional consequences in terms of myocyte dysfunction. In rats with pressure-overloaded ventricle, the same group had reported a permanent increase in total and polymerized tubulin that parallels the depression in contractile function (214). Controversial results were also reported by others. In pressure overload, in the guinea pig, neither the level of -tubulin nor its polymerized state appears to affect LV function (91). In rats, after aortic stenosis, an increased amount of polymerized microtubules was also observed; nevertheless, for these authors, such an augmentation was a transient phenomena that disappeared after 2-3 days (394).

Other cytoskeletal proteins could also play a role in maintaining a certain degree of cardiocyte stiffness. Titin, a giant protein (molecular mass 3 × 10⁶ Da), spans the sarcomeric Z line to M line and provides continuity for the production of force (reviewed in Ref. 243). Titin protein expression is enhanced both in experimental decompensated cardiac hypertrophy in guinea pig and in the failing human heart and may participate in the impairment of contractility (91, 310). Desmin forms ringlike bands around myofibrils at the level of the Z line and could serve as a three-dimensional scaffolding. Desmin is increased both in compensated and decompensated hypertrophy in the guinea pig and in CF in humans. In addition, in humans, desmin is disorderly arranged and -actinin localization is modified (91, 401). Vinculin anchors actin filaments via -actinin to the sarcolemma and intercalated disks and is a part of an attachment system of myofibers to external membrane. The amount of vinculin present in the cardiocytes is increased in dilated cardiomyopathy (401).

The microtubular modifications are load, chamber, and species specific (492) and, for the moment, the functional role of such a cytoskeleton structure has only been unequivocally demonstrated in feline right pressure overload. Changes in cytoskeleton components have only been observed using immunolabeling, and, in CF, it is, for the moment, impossible to decide whether the cytoskeleton components became apparent because of the high degree of cellular disorganization or if they represent a compensatory mechanism, thereby maintaining the cell shape (401).

	IV. PHENOTYPIC CHANGES IN THE EXTRACELLULAR MATRIX

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Fibrosis is an increased collagen concentration (18, 496). It enhances myocardial stiffness because collagen I is a very rigid protein (the tensile strength of collagen is 50-100 MPa and approaches that of steel), generates arrhythmias because fibrosis creates myocardial electrical heterogeneity, and hampers systolic ejection by rendering the myocardium heterogeneous. Myocardial fibrosis is probably one of the major biological determinant of fatal issues in CR, including congestive CF, severe arrhythmias, and sudden death; nevertheless, studies on myocardial fibrosis are still too rare when compared with studies on myocytes, and the majority of our information concerning myocardial fibrosis comes from one group (496).

It is common to identify two different types of fibrosis, namely, reparative and reactive fibrosis. Reparative fibrosis occurs as a reaction to a loss of myocardial material (due to necrosis or apoptosis, after myocardial ischemia or senescence), and it is mainly interstitial. In contrast, reactive fibrosis is observed in the absence of cell loss as a reaction to inflammation and is primarily perivascular. Reactive fibrosis further extends into the neighboring interstitial space (422). During CR, reactive and reparative fibrosis usually coexist.

There are converging reports suggesting that collagen mass, and not collagen concentration, increases in parallel with cardiac hypertrophy and the degree of mechanical overload. However, fibrosis occurs as an additional process and has different origins. Fibrosis is not directly induced by stretch or mechanical overload and does not participate in the adaptational process.

The ECM is composed of many different proteins, including collagen, the components of the pericellular matrix (fibronectin and proteoglycans), components of the basement membrane (laminin, collagen type IV), several proteases (including collagenases), and growth factors. The most important component is type I collagen, which is also the main component of fibrosis; it is synthesized and secreted mostly by the fibroblasts (but also by the smooth muscle cells) at an unusually low rate (it has a half-life of ~100 days) (reviewed in Refs. 131, 367, 496).

The ECM is a fibrillar network that embeds myofibers and the whole cardiac structure. It is normally subdivided into three components: the epimysium, which runs along epicardium and endocardium, the perimysium, which groups myofibers into bundles, and the endomysium, which surrounds individual myocytes and connects them to capillaries. Under normal conditions, the ECM, and more especially collagen I and the collagenases, is an important biological determinant of cardiac mechanics. 1 ) It is a structural component that maintains the alignment of myocytes and vessels and prevents myocyte slippage during contraction. 2) During systole it has an active functional role as a force transducer that facilitates relengthening. 3) As a passive functional component, it is the main determinant of diastolic stiffness (502).

More recently, emphasis has been made on other components of the ECM, such as fibronectin and laminin isoforms; integrins; the cell surface receptors, which are likely to play a role in transmembrane signaling; mitogen-activated protein (MAP) kinase activation; and cytoskeletal rearrangement, suggesting that the ECM is a less inert component than has been reported previously (131, 366, 367). The ECM is essential as a mediator of growth factor and in modulating the cell phenotype during ontogenic development and hypertrophy.

Fibrosis is multifactorial and is caused by myocardial ischemia or hypoxia, senescence (see sect. III), inflammatory processes, diabetes, hormones, or vasoactive peptides (Table 8) (497, 498).

2. Vasoactive peptides and hormone-induced myocardial fibrosis

A) VASOACTIVE PEPTIDES. Angiotensin II is fibrogenic, but the angiotensin II-induced fibrosis is much more complicated than previously expected because angiotensin II acts both as a growth factor and a potent vasoconstrictor. Angiotensin receptors have been identified both on cardiocytes and fibroblasts. The fibrogenic effect of angiotensin II involves several mechanisms, namely, cell death due to the vasoconstricting effect of the peptide responsible for ischemia, a direct trophic effect on the myocytes, and a proliferative effect on the fibroblasts (through the activation of TGF-).

Chronic administration of angiotensin II to normal rats for 2 wk causes arterial hypertension leading to LV hypertrophy and induces myocyte loss with microscopic scars that appear not only in the overloaded LV but also in the nonhypertrophied right ventricle (

Fibrosis is not inevitably linked to mechanical overload, and there are several experimental and clinical models of mechanically overloaded hearts with unchanged myocardial stiffness and collagen content (Table 9). This list is informative and helps improve our understanding of the physiopathology of cardiac fibrosis.

Chronic volume overload due to anemia (23, 395), arteriovenous fistula (301, 500), exercise training, atrial septal defect (279), or aortic insufficiency (12) is not accompanied by ventricular fibrosis. There are qualitative changes in collagen cross-linking in at least one of these conditions, aortic incompetence (210). Both the subendocardial myocardial collagen content and the degree of collagen cross-linking were reduced with the development of tachycardia-induced dilated cardiomyopathy. In contrast, in the same model with a 4-wk recovery period, both the collagen concentration and cross-linking increased with a significant enhancement of the interconnected collagen fibers (523).

There are also models of pressure overload hypertrophy without ventricular fibrosis. Clinical studies have suggested that an increased diastolic stiffness is associated with aortic stenosis in no more than half of the cases (350). Infrarenal aortic banding increases arterial pressure and LV weight to levels comparable to the most commonly used models of renal hypertension. Infrarenal aortic stenosis did not activate the glomerula and did not result in an elevation of either circulating angiotensin II or aldosterone, suggesting that these two hormones are responsible for ventricular fibrosis in renovascular hypertension or models with suprarenal aortic stenosis (53).

In this condition, fibrosis has to be clearly distinguished from the increased collagen content that occurs in response to mechanical overload and participates in the adaptational process. Pressure overload is frequently associated with fibrosis; nevertheless, as explained above, there are models of pressure overload with normal collagen concentration, and it has been proposed that ventricular fibrosis that is observed in this condition is caused by associated factors linked to arterial hypertension like ischemia, senescence, or diabetes, and plasma hormones or peptides (498). Renovascular hypertension, primary or secondary hyperaldosteronism, and CF are indeed clinical conditions that are associated with increased plasma levels of angiotensin II, aldosterone, and catecholamines (142). In contrast, clinical trials and experimental pharmacology have demonstrated a reduction in myocardial fibrosis when therapy was targeted to one of the corresponding receptors or to the secretion of angiotensin II (reviewed in Refs. 89, 90, 159, 326, 432).

In vitro, on an isolated working guinea pig heart, pressure overload activates myosin synthesis within 3 h; nevertheless, during such a lapse of time, collagen synthesis remains unchanged (406). In vivo, collagen mRNA concentration and the fractional turnover rate of collagen both increase rapidly following the imposition of pressure overload (41, 484) and nonmuscle cells proliferate, and it has been suggested that these modifications are consequences of both an activation of collagen synthesis and proliferation of fibroblasts (41, 319, 429).

Perinephritis in primates as well as renovascular hypertension or aortic stenosis in rats all result in reactive fibrosis. Unilateral renal ischemia, for example, rapidly gives rise to progressive perivascular fibrosis throughout the myocardium and from which fibrillar collagen extended into the extracellular space creating interstitial fibrosis and subendocardial microscopic scarring (75, 218, 326, 327, 422).

Rather ancient morphometric autopsy studies in humans have constantly demonstrated an increased collagen volume fraction with interstitial and perivascular fibrosis and microscopic scarring in hypertensive cardiopathy (reviewed in Refs. 403, 497). The increased percentage of fibrotic tissue is proportional both to the ventricular mass and ejection fraction until the threshold value of 250 g is reached. Above this value, the cardiac mass is no longer correlated with ventricular fibrosis, and the percentage of fibrosis reaches a plateau at ~30% (162). Clinical quantification of ventricular fibrosis has now been made possible by serum procollagen peptide measurements. The serum concentration of two procollagen peptides, procollagen type II amino terminal peptide and procollagen type I COOH-terminal peptide, is directly correlated with ventricular fibrosis during arterial hypertension (112, 287).

The origin of fibrosis is still a highly controversial issue. 1 ) There is no doubt that in conditions such as renovascular hypertension the high levels of plasma hormones and vasoactive peptides can generate fibrosis (see sect. IVB ). Nevertheless, there are models such as SHR with normal plasma angiotensin II or aldosterone and fibrosis. 2) As discussed in section VC, the local production of vasoactive peptides is likely to be another candidate. 3) The myocardial inflammatory cell density increases in two different models of experimental hypertension, SHR and renovascular hypertension, suggesting that such a cellular proliferation is directly linked to mechanical stretch. In both models, the inflammatory cells, including macrophages, T helpers, cytotoxic lymphocytes, and MHC class II-expressing cells (Ia+ cells), are colocalized with fibroblasts producing type I collagen, and it has been suggested that such infiltrates may cause fibrogenesis (202, 327, 328). Hence, it cannot be excluded that myocardial stretch and the presence of periarterial fibrosis in the nonoverloaded right ventricle could also be attributed to the intracoronary pressure overload as suggested by Michel and co-workers (326, 327). 4 ) A last hypothesis is that fibrosis could result from ischemia as a consequence of the reduction of coronary reserve. This hypothesis is supported by the findings of myocardial microscars in most of the models (326, 422).

Recent investigations using mRNA and protein quantitation on isolated muscle and nonmuscle cells and autoradiographic detection have revealed unusually large accumulations of ACE at sites of pathological fibrosis (74, 204, 373, 438; reviewed in Ref. 496). Such an anatomic coincidence was found in various models including MI, isoproterenol-induced cardiac hypertrophy, renovascular hypertension, and angiotensin II- or aldosterone-induced hypertrophy. High-density ACE binding was found in fibroblast-like cells, in scars, as well as in fibrous tissue far from the infarcted area and in the senescent fibrotic rat heart (199). Angiotensin II receptor subtype 1 is also associated with myocardial fibrosis after MI (373). Bradykinin receptor density is equally augmented in perivascular fibrosis and microscarrings in the angiotensin II- and aldosterone-induced models (496). Finally, unpublished data from our laboratory have demonstrated an increased expression of angiotensin II receptors, with a differential regulation of the two main subtypes, ATR1 and ATR2, both in the aldosterone-induced cardiac fibrosis and in the fibrotic senescence rat heart. Such an increase in the number of angiotensin II receptors is likely to occur both on the nonmuscular cells, where it reflects the high receptor density in fibroblasts, and in myocytes, as a result of volume overload.

	V. CELL DEATH

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Cell death is an important determinant of CR because it causes a loss of contractile tissue, compensatory hypertrophy of myocardial cells, and reparative fibrosis. Cell death may in fact be the only cause of fibrosis. A reduction of contractile material is a prominent feature in human CF whatever the origin and is accompanied by compensatory hypertrophy of myocytes and interstitial fibrosis (344, 401, 402).

Cell death can occur either by necrosis or apoptosis. The latter qualifies a genetically programmed cell death due to the activation of an endogenous endonuclease. The resulting DNA fragmentation produces a characteristic "ladder" when size-fractionated by electrophoresis. Apoptosis is associated with the expression of a number of regulatory genes commonly used as markers of apoptosis, including bcl-2, an antiapoptotic protooncogene, Fas, a proapoptotic gene, as well as others. In contrast to necrosis, apoptosis is commonly viewed by its requirement for de novo gene expression. Consequently, apoptosis is sensitive to mRNA or protein synthesis inhibitors. There are compelling evidences in support of reactive oxygen species (including superoxide and hydrogen peroxide)-induced apoptosis occurring not only during hypoxia or ischemia (474) but also after overstretch (78) and NO-induced apoptosis (356). Apoptosis plays an important role during development (220). During cardiac development, the rate of DNA degradation diminished and is inversely related to bcl-2 levels (228).

This topic is becoming very popular in cardiology (36) because apoptosis is rather easy to identify by the detection of DNA fragments in size multiples of 200 bp and by the expression of marker genes and preserved cytoplasmic structures, although these three (or at least the first two) criteria have rarely been met. Necrosis is characterized by severe membrane alterations and is preceded by a period of time during which the diseased cells become permeable to immunoglobulins such as radioactive monoclonal antibodies raised against myosin. Uninjured cells remain unlabeled.

Surprisingly, the main cause of cellular loss during myocardial ischemia is not necrosis but apoptosis. In vitro studies using cultured neonatal cardiocytes exposed to hypoxia or ischemia for 8-12 h clearly demonstrated a mixed phenotype which associates necrotic and apoptotic cells. Apoptotic cells were observed during the ischemic period but were more abundant once normal oxygen and glucose conditions (which is equivalent to reperfusion) were restored (474).

In vivo experimental and clinical investigations have confirmed such in vitro findings, strongly suggesting that apoptosis could be, in association with necrosis, an important component of post-MI. The pioneering study of Gottlieb et al. (161) demonstrated apoptosis after reperfusion in a rabbit model of myocardial ischemia. A careful evaluation of the respective roles of these two modes of cell death was performed by Kajstura et al. (226) in the rat model of MI and led to the conclusion that during the first 6 h after coronary occlusion programmed cell death is the major form of myocardial damage (representing >90% of the dying cells). Necrotic cells prevailed at later times (2 days), and a similar small number of apoptotic and necrotic cells were observed on the seventh day. Studies of myocardial samples from patients who died from acute MI showed typical apoptotic myocytes mainly in the border zone of the infarcted myocardium and confirmed the predominance of apoptotic compared with necrotic cells (397, 480).

Involvement of apoptosis in the development of ventricular hypertrophy was first demonstrated by Teiger et al. (463). Thoracic aortic banding in rats results in cardiac hypertrophy without failure and in a wave of apoptosis, mainly in cardiocytes, which peaks by the seventh day. It has subsequently been suggested that apoptosis is a regulatory mechanism that participates in the initiation of the hypertrophic process. Apoptosis, as a consequence of stretch (78), may in fact result from the overall systemic arterial overload as has been demonstrated in nearly every organ, including the heart, kidney, and brain, in two experimental models of arterial hypertension, the SHR model, and the genetically hypertensive mice (175).

A few reports have recently shown an increased number of apoptotic cardiocytes in failing hearts. It is for the moment impossible to decide whether apoptosis is the cause or a consequence of CF. Fragmentation and laddering of DNA have been demonstrated during cardiac transplantation in all patients with dilated cardiomyopathy. In ischemic cardiopathy, apoptotic cells were not observed in the nonischemic area, but only in the infarcted zone (320). In the transition model of aging SHR, apoptotic cells in association with increased levels of WAF-1 mRNA were nearly fivefold more abundant in the failing than in the nonfailing hearts, suggesting that apoptosis might be a mechanism involved in the reduction of myocyte mass that accompanies the transition from compensated hypertrophy to CF (252).

An increased plasma level of angiotensin II and catecholamine is observed during CR either as a compensatory mechanism in response to decreased systemic blood pressure and flow or as a marker of certain etiologies such as renovascular hypertension or pheochromocytoma. Pharmacological and pathophysiological levels of angiotensin II and catecholamines produce myocyte necrosis and coronary artery damage (116, 150, 460). Necrosis is observed within the first 3 days of angiotensin II infusion before the elevation of plasma norepinephrine levels and is prevented by both losartan and propranolol, suggesting that it is caused by angiotensin II-induced release of neural catecholamines within the heart (195). Angiotensin II directly antagonized NO donor-induced apoptosis (356).

Pioneer studies have demonstrated that subcutaneous administration of isoproterenol produces graded myocardial necrosis and reduction in cardiac performance (reviewed in Ref. 380). Further investigations in rats have revealed a dose-dependent increase in ventricular end-diastolic pressure, volume indexes, diastolic stiffness, and global wall stress that are associated with compensatory hypertrophy and reparative fibrosis (462).

	VI. CHANGES IN GENE EXPRESSION IN RELATION TO MYOCARDIAL FUNCTION

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Changes in myocardial function precede the end stage of CF; failure obviously indicates the limits and imperfections of the adaptational process and is dependent on both myocardial and peripheral factors. Recent advances in the biology of cardiac hypertrophy and failure have allowed one to separate three groups of trophic factors that act independently, namely, the adaptational process to the new hemodynamic conditions, factors linked to etiology, and neuroendocrine reactions. Each of these factors plays a role in the genesis of the abnormalities in cardiac function, i.e., systolic and diastolic dysfunction, and arrhythmias. The mechanisms leading to arrhythmias are much more complex than those responsible for systolic and diastolic function.

Clinically detectable alterations in systolic ejection and active relaxation occur later in vivo than in vitro and can be observed on a papillary muscle or by biochemical or molecular biological methods (7, 246, 247). The alterations in systolic function are initially adaptational, but they also simultaneously indicate the beginning of failure. The cardiac output can be maintained by several compensatory mechanisms including Starling's law, peripheral adaptation, and the sympathetic drive.

In rat ventricles, the shift in ventricular isomyosins is correlated with the shortening velocity (412); nevertheless, there is also evidence that the calcium movements are altered in parallel (7, 481). In the human ventricle, there are no significant isomyosin shifts (49, 245), and the adaptation is more likely to be due to a slowing of the calcium transient, which is itself determined by changes in the expression of genes encoding membrane proteins. Other sarcomeric mechanisms have been proposed (205, 206, 509).

When passive compliance is altered by fibrosis, atrial contraction plays an important role in compensating for the deficiency in ventricular filling as shown by echo-Doppler. Atrial contractility is mainly under the control of the contractile proteins and depends on the myosin ATPase activity and the type of isomyosin present in the atria. During hemodynamic overload, the composition of the atria changes from 100% V1 to 100% V3 isoform (292, 470). From a thermodynamic point of view, such an isomyosin shift can be considered as a compensatory mechanism that allows the atria to maintain an increased output at a low energy cost.

Fibrosis is also one of the determinants of systolic function that is impaired by myocardial heterogeneity, and also by the encircling of myofibers that imposes a physical restraint on muscle distension, as shown in the rat in a model which associates both reparative and reactive fibrosis (218).

Left ventricular diastolic dysfunction in cardiac hypertrophy results from two different factors, namely, the alterations in active relaxation which in turn depends on the biological process of adaptation and the changes in diastolic compliance which are direct consequences of chamber diameter and collagen concentration (62). Ventricular chamber compliance (the pressure-volume curve) depends on the ventricular diameter. Ventricular tissue compliance (the stress-strain curve) is determined by collagen concentration and the degree of fibrosis (146).

Several experimental designs have investigated the importance of collagen content and distribution on myocardial mechanics. 1 ) In rats, using different models that provide a wide range of collagen concentrations and distributions, Jalil et al. (218) have demonstrated that passive stiffness, measured in vitro on Langendorff-perfused hearts, parallels collagen volume fraction. Passive stiffness rose disproportionately when >15% of the myocardium was occupied by collagen. 2) Investigations carried out on the isoproterenol model in rats have revealed a dose-dependent increase in ventricular end-diastolic pressure, volume indexes, diastolic stiffness, and global wall stress that is associated with compensatory hypertrophy and reparative fibrosis (462). 3) Lathyrogen-B aminoproprionitrile, a component which hampers collagen synthesis, prevents changes in diastolic stiffness induced by aortic banding (39). 4 ) Perfusion of isolated hearts with bacterial collagenase for 60 min resulted in low collagen content, ventricular dilatation, and changes in chamber stiffness (289). Diastolic dysfunction reduces the passive ventricular filling. Such a reduction is compensated by an enhanced atrial contribution (146).

Sudden death, presumably related to severe arrhythmias, accounts for at least 50% of deaths among patients with CF. Interestingly, the high incidence of arrhythmias in CF is unrelated to ischemic heart diseases. In addition, epidemiological surveys and animal experiments have shown a high incidence of benign arrhythmias in CCH (19, 80, 251, 447). Several attempts have been made to predict severe arrhythmias by using various indexes including heart rate, heart rate variability, and Q-T interval.

The biological substrate for arrhythmogenicity in CR is a complex issue (19, 447). Fibrosis and changes in the membrane protein composition are both essential during the compensated phase. Additional factors including plasma catecholamines and ventricular dilatation are involved during CF.

The shorter and less controversial definition of CF is "ventricular dysfunction with symptoms" (discussed in detail in Ref. 358), which means that CF is a disease state with both abnormalities in the myocardial structure (i.e., CR) and clinical symptoms due to fluid retention (i.e., tachypnea, edema, and congestion of liver). The severity of the disease is commonly appreciated using the NYHA classification, which is entirely based on functional symptoms. Cardiac remodeling is most commonly caused by MI and/or arterial hypertension, i.e., by LV overload; consequently, the most commonly observed early symptom of CF is dyspnea initially during exercising and then at rest. Such a clinical symptom indicates that the ejection fraction is altered and that the end-diastolic pressure starts to increase.

The functional nature of such a definition renders the experimental approach of the transition difficult. It is indeed difficult to quantitate tachypnea in a rat. Schematically, the heart can fail for three reasons. 1 ) Failure may indicate the limits of the above-defined adaptational process. Every phenotypic modification has a limit, e.g., the beneficial effects, in terms of myocardial economy, of the isomyosin shift are maximum when the fast myosin (V1) has been completely replaced by the slow isoform (V3). 2) Fibrosis whether it is caused by the trophic effects of vasoactive peptides, senescence, or ischemia can play a crucial role, even if the adaptational process does not reach its limits. 3) Finally, failure can be caused by a loss of muscle due to necrosis or apoptosis. In fact, the three reasons are frequently associated although to various degrees; several months after MI, the decrease in ejection fraction is caused by a combination of fibrosis, loss of substance, and inability of the adaptational process to compensate.

There are no specific biological markers for CF. Cardiac failure depends on a myocardial deficit, but the hemodynamic consequences can be entirely masked by the compensatory effects of peripheral factors. In addition, in terms of cellular biology, failure depends on the whole activity of the cells and tissue and is not the consequence of the deficit of one particular molecule.

The transition from compensated to decompensated cardiac hypertrophy has in fact been rather rarely studied. There are for the moment only few experimental models that allow such an analysis. 1 ) Spontaneously hypertensive rats develop impaired myocardial function and biventricular congestive CF at the age of 18 mo after a long period of CCH due to arterial hypertension. Aging SHR provide a reproducible although rather expensive model, and one of the determinants of CF is senescence. Fifty-seven percent of a group of 30 18- to 24-mo-old male SHR developed clinical evidence of decompensation, and only 13% survived to 24 mo. Pathological assessment of CF shows left and right ventricular hypertrophy that is associated with liver hypertrophy and pleuropericardial effusions, and studies on myocardial function have revealed impaired systolic function, increased end-diastolic volume, and diastolic stiffness (38, 468). 2) Dahl salt-sensitive rats fed with a high-salt diet after the age of 6 wk developed concentric LV hypertrophy at 11 wk and CF with ventricular dilatation and increased plasma concentration in norepinephrine at 15-20 wk. In failing hearts, isometric contractions of the papillary muscle have shown a reduced contractility, and histological quantification has revealed modest subendocardial and perivascular ventricular fibrosis probably because of the age of the animals (213). 3) Stenosis of the descending aorta in guinea pigs results in some cases in congestive CF with an increased lung-to-body weight ratio. Animals with normal lungs had unchanged myocardial performance (232), which is different from what is observed in the nonfailing SHR (37). 4 ) Myocardial infarction in young rats gives rise to diastolic and systolic congestive failure and pronounced alterations of ventricular compliance (299, 352). The model is widely used but is not so easy as a model to study transition because the failing period is rather unpredictable.

Search for molecular markers of the transition are for the moment only beginning. In the SHR model, molecular biology has shown a progressive decline in the amount of the -MHC isoform and SR Ca²⁺-ATPase and an increase in ANF when compared with control, compensated hypertrophic, and failing hearts. Nevertheless, the only real markers of failure, i.e., the only probes which really allow one to distinguish between compensated and decompensated states, are probes specific for the ECM components, i.e., fibronectin (specially the EIIIA+ isoform), pro-₁(I) and (III) collagen isoforms, and TGF-1, and it was proposed that mechanical overload can directly or indirectly activate the fibroblastic gene expression of TGF-1 and that failure occurs through this pathway when fibrosis reaches a certain level (47). Another biological marker of the transient that has been proposed is the disappearance of the sensitivity to -agonists (37). The markers can differ from one model to another; in guinea pig after aortic banding, the Ca²⁺-ATPase of SR remains unchanged in compensated hypertrophy and is only modified in CF (232).

	VII. CARDIAC REMODELING DUE TO SENESCENCE

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Studies on cardiovascular senescence are far from being academic, since epidemiological studies have shown that CR is the main cause of mortality in people over 65 yr of age. Therefore, it is of major importance to assess the limits of normality during aging. The clinical problem is far from being simple because the fundamental biological process of senescence is intimately associated with an increased incidence of arterial hypertension, atherosclerosis, and modifications in physical activity and nutritional status, which all may seriously modify the myocardial structure.

This subject has already been extensively reviewed (32, 138, 140, 244). Therefore, we only summarize the main differences and similarities that exist between the normal senescent heart and the overloaded heart (Table 10). Cardiac overload has frequently been considered as a prematurely aged heart, which is obviously incorrect (32). From a biological point of view, the modifications of the senescent heart result from three different factors, including the general process of senescence, the senescence of the endocrine system, and above all the senescence of the vessels (the increased characteristic aortic impedance which creates a LV overload).

The senescent heart, in the absence of arterial hypertension and coronary insufficiency, is in many respects comparable to LV overload. As such, it contracts more economically (31), and this is caused by the same phenotypic modifications of contractile and membrane proteins as in the pressure-overloaded heart, including the ventricular isomyosin change in rats, the modifications of the external membrane and sarcoplasmic reticulum proteins, and the activation of ANF and RAS (199, 200, 240, 458) (Table 10). An interesting finding, made in humans (183), is that the force-time integral of the individual myosin cross-bridge cycle is correlated with the age of the patient with nonfailing myocardium, suggesting that, even in humans, aging is also associated with an improvement of contraction economy.

The blunted response of the autonomous nervous system to exercising is a well-documented finding (166, 244) and is accompanied by a reduction in the density of both -adrenergic and muscarinic receptors. However, the decrease in muscarinic receptor density is greater than that in total -adrenergic receptors (82, 166, 179, 180). A similar decrease in the number of muscarinic receptors has also been reported in the cerebral cortex, striatum, and hippocampus, suggesting that, for unknown reasons, aging has a rather specific and pronounced effect on the muscarinic system (104).

Finally, the modifications in both protein synthesis and degradation and mRNA content that occur during aging (104) would suggest that the senescent heart may also be unable to adapt to an increased load. Several experimental investigators have tried to answer this question. The general opinion is that the senescent heart responds more slowly to mechanical overload than the young heart but that the final result is the same in terms of myocardial mass (31, 69, 215).

Clinical, epidemiological, and experimental studies have demonstrated a prevalence of supraventricular and ventricular ectopic beats and an attenuation of heart rate variability (71, 138, 251). Arrhythmias result from both fibrosis and changes in the membrane phenotype responsible for the increased duration of the action potential and calcium transient.

The aging heart contains less myocytes than younger hearts (11). On the basis of autopsy findings, it has been suggested that the process is gender specific and does not occur in women (339). The cause of death includes both ischemic necrosis due to the age-related reduction in coronary reserve and apoptosis that is temporally and spatially unrelated to necrosis. Necrosis is the predominant cause of cell death; quantification has indeed shown that there are ~1,000 times more necrotic cells than apoptotic cells. Apoptosis during aging is localized into the left ventricle, suggesting that it is initiated by mechanical factors (227).

Myocardial fibrosis is also a constant finding in healthy senescent hearts both in rats and humans (11, 31, 33, 122, 274, 339). Cardiac fibrosis in this condition is certainly, at least in part, a reparative process related to myocyte death and predominates in the subendocardium. Nevertheless, the regulation of myocardial concentration during aging is a complex phenomenon. Two different studies have provided converging results and have shown a paradoxically inverse relationship between the protein and mRNA content of collagen in aging hearts; the lower the mRNA concentration, the higher the protein levels (33, 122), which is in contrast to the situation observed with fibronectin (274). In addition, a 40-45% diminution of both collagenase MMP2 and MMP1 has recently been evidenced in 22- to 24-mo-old rats, suggesting that collagen accumulation is, at least in part, regulated at the level of the degradative pathway, which is in contrast to the situation observed in the aldosterone model (375).

Aging also modifies the endocrine system and is associated with an increased plasma level of cortisol and low plasma levels of free thyroxine (but 3,3',5-triiodothyronine is unchanged), angiotensin I and II, renin activity, and angiotensinogen (199, 200), which is clearly different from the situation observed in pressure overload. In contrast, during aging, the angiotensinogen and ACE myocardial mRNA levels are both upregulated. This upregulation is restricted to the left ventricle and does not exist in the right ventricle (97, 199). The specific LV activation of these normally poorly expressed genes suggests that the trigger for activation is a LV mechanical overload.

Cardiac failure is mainly a disease of the elderly, and the average age of the patients in most of the clinical trials is ~70 yr (93, 430). Obviously, most of the patients under CEI have a low plasma level of angiotensin II, and the question is how such a therapy works in the elderly? The answer is most likely to be found in the various tissue systems, at least the ones located in the myocardium.

To conclude, the senescent heart, even in the absence of arterial hypertension or coronary insufficiency, is potentially a diseased heart. Myocardial function in the elderly is still normal because of the various adaptational mechanisms (19). As such, it resembles CCH occurring before NYHA stage I during the course of an arterial hypertension.

	VIII. CONCLUSION

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To conclude, 1 ) CR is a rather complex issue and results from interactions between mechanical factors that cause adaptational modifications of the cardiocyte, and numerous etiologic, epidemiological, or neurohormonal factors that all are capable of modifying the cardiocyte phenotype can cause cell death and trigger the fibrotic process (Fig. 5). 2) The slowing of the shortening velocity is a consequence of the general process of adaptation and is independent of changes in the ECM changes. Nevertheless, chronic congestive CF rarely occurs in the absence of additional factors, namely, fibrosis or cell death. 3) In clinical practice, CR and CF are diseases of aging people with MI and/or arterial hypertension. From a biological point of view, cardiocyte modifications, cell death, and fibrosis are associated in the failing human heart. More information is needed to appreciate the exact role of cell death. Fibrosis renders the myocardium stiffer and mechanically and electrically heterogeneous, and this plays a crucial role in the genesis of arrhythmias and deterioration of both systolic and diastolic function. For the moment, therefore, fibrosis is the best marker of CF.

View larger version (18K): [in this window] [in a new window]   FIG. 5.   Biological determinants of cardiac remodeling: a scheme. Initial event is "mechanical stress," which in fact is myocardial infarction (MI) and/or arterial hypertension. In practice, stress is rarely acute and generally progressive. After MI, main stress is stretch around scar. Mechanical stress modifies genetic expression directly or through activation of myocardial autocrine function. RAS, renin-angiotensin system. 1 ) Adaptational process is basically beneficial and improves muscular economy; nevertheless, and simultaneously, process has also potentially deleterious consequences (i.e., slowing of shortening veloctiy simultaneously allows heart to produce normal active tension and is first step of reduction of cardiac output). 2) Another heterogeneous group of factors is specific for certain etiologies (senescence, ischemia) or due to hemodynamic deficit (and then proportional to severity of cardiac failure). Such factors cause fibrosis and cell death and also may modify phenotype of myocytes due to trophicity of several hormones or peptides (see Table 3), have deleterious consequences on myocardial functions, and modify adaptational program. 3) Both processes are simultaneous in clinical conditions.

Future researches will certainly benefit from the recent developments in genome-based methods. Recently, using one of these methods, the expressed sequence tags (EST), Liew's group in Toronto (209) published the first publicly available database of human cardiovascular containing 43,285 EST; of these, 55% matched to known genes in specific database. Comparisons between different specific cardiac libraries allowed the identification of 34 genes that were overexpressed in cardiac hypertrophy, including mitochondrial genome transcripts, MLC2, brain natriuretic peptide, desmin, 70-kDa heat-shock protein, superoxide dismutase, ANF, -tropomyosin, and -actin. Several unexpected overexpressed genes were also discovered, including ribosomal proteins, TIMP-4, prostaglandin D synthase, strongly suggesting that the methodology holds tremendous potential for genome-wide research for novel genes involved in CR. Several other techniques are already available, including DNA microarrays (111), mRNA differential displays (253, 493), or the serial analysis of gene expression (524), and it is easy to predict that we should soon have information concerning the whole pattern of expressed sequences during the various steps of CR instead of disperse informations such as those presently available.

Another important, and poorly explored, issue consists of studying the trophic effects of both various hormones and vasoactive peptides and different etiologic conditions in experimental models of cardiac overload. Such trophic effects have indeed been fully documented in undiseased adult animals, but we need experimental protocols trying to mimic the clinical conditions, namely, pure mechanical overload plus a continuous infusion of either catecholamines or angiotensin II, or mechanical overload in experimental models of senescence (see sect. VIIA ). Another still unexplored condition is ischemia plus mechanical overload, since it has recently been shown that ischemia alone can change gene expression (20) and therefore modify the phenotype obtained by mechanical overload (see Table 3).

	ACKNOWLEDGEMENTS

  I thank Gill Butler-Brown, Danièle Charlemagne, Edouard Coraboeuf, Alain Cohen-Solal, and Lydie Rappaport for rereadings and/or helpful discussions during the preparation of the manuscript.

	REFERENCES

Top Previous

1.   ABRAHAM, W. T., J. D. PORT, AND M. R. BRISTOW. Neurohormonal receptors in the failing heart. In: Heart Failure, edited by P. A. Poole-Wilson, W. S. Colucci, B. M. Massie, K. Chatterjee, and A. J. S. Coats. New York: Churchill Livingstone, 1997, p. 127-141.

2.   ADLER, C. P. Relationship between DNA content and nucleoli in human heart cells and estimation of cell number during cardiac growth and hyperfunction. In: Recent Advances in Studies on Cardiac Structure and Metabolism. The Cardiac Sarcoplasm, edited by P. E. Roy and P. Harris. Baltimore, MD: University Park Press, 1975, p. 373-386.

3.   ALGRA, A., J. G. P. TIJSSEN, J. R. T. C. ROELANDS, J. POOL, AND J. LUBSEN. QTc prolongation measured by standard 12-lead electrocardiography is an independent risk factor for sudden death due to cardiac arrest. Circulation 83: 1888-1894, 1991.

4.   ALLARD, M. F., S. L. HENNING, R. B. WAMBOLT, S. R. GRANLEESE, D. R. ENGLISH, AND G. D. LOPASCHUK. Glycogen metabolism in the aerobic hypertrophied rat heart. Circulation 96: 676-682, 1997.

5.   ALPERT, N. R., AND M. S. GORDON. Myofibrillar adenosine triphosphatase activity in congestive heart failure. Am. J. Physiol. 202: 940-946, 1962.

6.   ALPERT, N. R., AND L. A. MULIERI. Increased myothermal economy of isometric force generation in compensated cardiac hypertrophy induced by pulmonary artery constriction in the rabbit: a characterization of heat liberation on normal and hypertrophied right ventricular papillary muscles. Circ. Res. 50: 491-500, 1982.

7.   ALPERT, N. R., L. A. MULIERI, AND G. HASENFUSS. Myocardial chemo-mechanical energy transduction. In: The Heart and Cardiovascular System, edited by H. A. Fozzard, E. Haber, A. M. Katz, R. Jennings, and H. Morgan. New York: Raven, 1992, p. 111-128.

8.   ANDERSON, K. P., R. WALKER, P. URIE, P. R. ERSHLER, R. L. LUX, AND S. V. KARWANDEE. Myocardial electrical propagation in patients with idiopathic dilated cardiomyopathy. J. Clin. Invest. 92: 122-140, 1993.

9.   ANDERSON, P. A. W., N. N. MALOUF, A. F. OAKELEY, E. D. PAGANI, AND P. D. ALLEN. Troponin T isoform expression in humans. A comparison among normal and failing heart, fetal heart and adult and fetal skeletal muscle. Circ. Res. 69: 1226-1233, 1991.

10.   ANKER, S. D., T. P. CHUA, P. PONIKOWSKI, D. HARRINGTON, J. W. SWAN, W. J. KOX, P. A. POOLE-WILSON, AND A. J. COATS. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation 96: 526-534, 1997.

11.   ANVERSA, P., T. PALACKAL, E. H. SONNENBLICK, G. OLIVETTI, L. G. MEGGS, AND J. M. CAPASSO. Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ. Res. 67: 871-885, 1990.

12.   APSTEIN, C., Y. LECARPENTIER, J.-J. MERCADIER, J. L. MARTIN, F. PONTET, C. WISNEWSKY, K. SCHWARTZ, AND B. SWYNGHEDAUW. Changes in LV papillary muscle performance and myosin composition with aortic insufficiency in rats. Am. J. Physiol. 253(Heart Circ. Physiol. 22): H1005-H1011, 1987.

13.   ARAI, M., N. R. ALPERT, D. H. MCLENNAN, P. BARTON, AND M. PERIASAMY. Alterations in sarcoplasmic reticulum gene expression in human heart failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. Circ. Res. 72: 463-469, 1993.

14.   ARAI, M., H. MATSUI, AND M. PERIASAMY. Sarcoplasmic reticulum gene expression in cardiac hypertrophy and heart failure. Circ. Res. 74: 555-564, 1994.

15.   ARONSON, R. S.. Characteristics of action potentials of hypertrophied myocardium from rats with renal hypertension. Circ. Res. 47: 443-454, 1980.

16.   ARONSON, R. S.. Afterpotentials and triggered activity in hypertrophied myocardium from rats with renal hypertension. Circ. Res. 48: 720-727, 1981.

17.   ASANO, K., D. L. DUTCHER, D. PORT, W. A. MINOBE, K. D. TREMMEL, R. L. RODEN, T. J. BOHLMEYER, E. W. BUSH, M. J. JENKIN, W. T. ABRAHAM, M. V. RAYNOLDS, L. S. ZISMAN, M. B. PERRYMAN, AND M. R. BRISTOW. Selective downregulation of the angiotensin II AT1-receptor subtype in failing human ventricular myocardium. Circulation 95: 113-120, 1997.

18.   ASSAYAG, P., F. CARRÉ, B. CHEVALIER, C. DELCAYRE, P. MANSIER, AND B. SWYNGHEDAUW. Compensated cardiac hypertrophy. Arrhythmogenecity and the new myocardial phenotype. Part 1: Fibrosis. Cardiovasc. Res. 34: 439-444, 1997.

19.   ASSAYAG, P., D. CHARLEMAGNE, J. DE LEIRIS, F. BOUCHER, P.-E. VALERE, S. LORTET, B. SWYNGHEDAUW, AND S. BESSE. Senescent heart as compared to pressure overload induced hypertrophy. Hypertension 29: 15-21, 1997.

20.   ASSAYAG, P., D. CHARLEMAGNE, I. MARTY, J. DE LEIRIS, A.-M. LOMPRÉ, F. BOUCHER, P.-E. VALÈRE, S. LORTET, B. SWYGHEDAUW, AND S. BESSE. Effects of sustained low-flow ischemia on myocardial function and calcium-regulating proteins in adult and senescent rat hearts. Cardiovasc. Res. 38: 169-180, 1998.

21.   ASTORRI, E., R. BOLOGNESI, B. COLLA, A. CHIZZOLA, AND O. VISIOLI. Left ventricular hypertrophy: a cytometric study on 42 human hearts. J. Mol. Cell. Cardiol. 9: 763-775, 1977.

22.   BAKER, K. M., M. I. CHERNIN, S. K. WIXSON, AND J. F. ACETA. Renin-angiotensin system involvement in pressure-overload cardiac hypertrophy in rats. Am. J. Physiol. 259(Heart Circ. Physiol. 28): H324-H332, 1990.

23.   BARTOSOVA, D., M. CHVAPIL, B. KORECKY, O. POUPA, K. RAKUSAN, Z. TUREK, AND M. VIZEK. The growth of the muscular and collagenous parts of the rat heart in various forms of cardiomegaly. J. Physiol. (Lond.) 200: 285-295, 1969.

24.   BASTIDE, B., L. NEYSES, D. GANTEN, M. PAUL, K. WILLECKE, AND O. TRAUB. Gap junction protein connexin 40 is preferentially expressed in vascular endothelium and conductive bundles of rat myocardium and is increased under hypertensive conditions. Circ. Res. 73: 1138-1149, 1993.

25.   BASTIE DE LA, D., D. LEVITSKY, L. RAPPAPORT, J. J. MERCADIER, F. MAROTTE, C. WISNEWSKY, V. BROKOVICH, K. SCHWARTZ, AND A. M. LOMPRÉ. Function of the sarcoplasmic reticulum and expression of its Ca²⁺ ATPase gene in pressure overload-induced cardiac hypertrophy in the rat. Circ. Res. 66: 554-564, 1990.

26.   BASTIE DE LA, D., J. M. MOALIC, P. BOUVERET, K. SCHWARTZ, AND B. SWYNGHEDAUW. Messenger RNA content and complexity in normal and overloaded rat heart. Eur. J. Clin. Invest. 17: 194-201, 1987.

27.   BAUMGARTEN, C. R., W. LINZ, G. KUNKEL, B. A. SCHOLKENS, AND G. WIENER. Ramaprilat increases bradykinin outflow from isolated hearts of rat. Br. J. Pharmacol. 108: 293-295, 1993.

28.   BAUTERS, C., J. M. MOALIC, J. BERCOVICI, C. MOUAS, R. EMANOIL-RAVIER, S. SCHIAFFINO, AND B. SWYNGHEDAUW. Coronary flow as a determinant of c-myc and c-fos proto-oncogene expression in an isolated adult rat heart. J. Mol. Cell. Cardiol. 20: 97-101, 1988.

29.   BENITAH, J. P., A. M. GOMEZ, P. BAILLY, J. P. DA PONTE, G. BERSON, C. DELGADO, AND P. LORENTE. Heterogeinity of the early outward current in ventricular cells isolated from normal and hypertrophied rat ventricles. J. Physiol. (Lond.) 469: 11-138, 1993.

30.   BERRIDGE, M. J., AND R. F. IRVINE. Inositol triphosphate, a novel second messenger in cellular signal transduction. Nature 312: 315-321, 1984.

31.   BESSE, S., P. ASSAYAG, C. DELCAYRE, F. CARRE, S. L. CHEAV, Y. LECARPENTIER, AND B. SWYNGHEDAUW. Normal and hypertrophied senescent rat heart. mechanical and molecular characteristics. Am. J. Physiol. 265(Heart Circ. Physiol. 34): H183-H190, 1993.

32.   BESSE, S., C. DELCAYRE, B. CHEVALIER, S. HARDOUIN, C. HEYMES, F. BOURGEOIS, J.-M. MOALIC, AND B. SWYNGHEDAUW. Is the senescent heart overloaded and already failing? a review. Cardiovasc. Drugs Ther. 8: 581-587, 1994.

33.   BESSE, S., V. ROBERT, P. ASSAYAG, C. DELCAYRE, AND B. SWYNGHEDAUW. Non-synchronous changes in myocardial collagen mRNA and protein during aging. Effect of DOCA-salt hypertension. Am. J. Physiol. 267(Heart Circ. Physiol. 36): H2237-H2244, 1994.

34.   BEUCKELMANN, D. J., M. NÄBAUER, AND E. ERDMANN. Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation 85: 1046-1055, 1992.

35.   BEUCKELMANN, D. J., M. NÄBAUER, AND E. ERDMANN. Alterations of K⁺ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ. Res. 73: 379-385, 1993.

36.   BING, O. H. L.. Hypothesis: apoptosis may be a mechanism for the transition to heart failure with chronic pressure overload. J. Mol. Cell. Cardiol. 26: 943-948, 1994.

37.   BING, O. H. L., W. W. BROOKS, C. H. CONRAD, S. SEN, C. L. PERREAULT, AND J. P. MORGAN. Intracellular calcium transients in myocardium from spontaneously hypertensive rats during the transition to heart failure. Circ. Res. 68: 1390-1400, 1991.

38.   BING, O. H. L., W. W. BROOKS, K. G. ROBINSON, M. T. SLAWSKY, J. A. HAYES, S. E. LITWIN, S. SEN, AND C. H. CONRAD. The spontaneously hypertensive rat as a model of the transition from compensated left ventricular hypertrophy to failure. J. Mol. Cell. Cardiol. 27: 383-396, 1995.

39.   BING, O. H. L., B. L. FANBURG, W. W. BROOKS, AND S. MATSUSHITA. The effect of the lathyrogen-B amino proprionitrile (BAPN) on the mechanical properties of experimentally hypertrophied rat cardiac muscle. Circ. Res. 43: 632-637, 1978.

40.   BING, R. J., C. WU, S. GUDBJARNASON, H. TSCHOPP, AND W. BRAASCH. Molecular changes in myocardial infarction in heart failure. Ann. NY Acad. Sci. 156: 583-593, 1969.

41.   BISHOP, J. E., S. RHODES, G. J. LAURENT, R. B. LOW, AND W. S. STIREWALT. Increased collagen synthesis and decreased collagen degradation in right ventricular hypertrophy induced by pressure overload. Cardiovasc. Res. 28: 1581-1585, 1994.

42.   BOHELER, K. R., L. CARRIER, D. DE LA BASTIE, P. D. ALLEN, M. KOMAJDA, J. J. MERCADIER, AND K. SCHWARTZ. Skeletal actin mRNA increases in the human heart during ontogenic development and is the major isoform of control and failing adult hearts. J. Clin. Invest. 88: 323-330, 1991.

43.   BOHELER, K. R., C. CHASSAGNE, X. MARTIN, C. WISNEWSKY, AND K. SCHWARTZ. Cardiac expressions of  and  myosin heavy chains and sarcomeric alpha actins are regulated through transcriptional mechanisms: results from nuclear run-on assays in isolated rat cardiac nuclei. J. Biol. Chem. 267: 12979-12985, 1992.

44.   BÖHM, M., D. BEUCKELMAN, L. BROWN, G. FEILER, B. LORENZ, M. NÄBAUER, B. KEMKES, AND E. ERDMANN. Reduction of beta-adrenoceptor density and evaluation of positive responses in isolated, diseased human myocardium. Eur. Heart J. 9: 844-852, 1988.

45.   BÖHM, M., P. GIERSHIK, K. H. JAKOBS, B. PIESKE, P. SCHNABEL, M. UNGERER, AND E. ERDMANN. Increase of G_i in human hearts with dilated but not ischemic cardiomyopathy. Circulation 82: 1249-1265, 1990.

46.   BÖHM, M., B. PIESKE, M. UNGERER, AND E. ERDMANN. Characterization of A₁ adenosine receptors in human atrial and ventricular myocardium from diseased human hearts. Circ. Res. 65: 1201-1211, 1989.

47.   BOLYUT, M. O., L. O'NEILL, A. L. MEREDITH, O. H. L. BING, W. W. BROOKS, C. H. CONRAD, M. T. CROW, AND E. G. LAKATTA. Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure. Marked upregulation of genes encoding extracellular matrix components. Circ. Res. 75: 23-32, 1994.

48.   BONNE, G., L. CARRIER, J. BERCOVICI, C. CRUAUD, P. RICHARD, B. HAINQUE, M. GAUTEL, S. LABEIT, M. JAMES, J. BECKMANN, J. WEISSENBACH, H.-P. VOSBERG, M. FISZMAN, M. KOMAJDA, AND K. SCHWARTZ. Cardiac myosin binding protein C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy. Nature Genet. 11: 438-440, 1995.

49.   BOUVAGNET, P., J. LÉGER, C. A. DECHESNE, G. DUREAU, M. ANOAL, AND J. J. LÉGER. Local changes in myosin types in diseased human atrial myocardium: a quantitative immunofluorescence study. Circulation 72: 272-279, 1985.

50.   BOUVAGNET, P., J. LÉGER, F. PONS, C. A. DECHESNE, AND J. J. LÉGER. Fiber types and myosin types in human atrial and ventricular myocardium. An anatomical description. Circ. Res. 55: 794-804, 1984.

51.   BOUVAGNET, P., S. NEVEU, M. MONTOYA, AND J. J. LÉGER. Developmental changes in the human cardiac isomyosin distribution: an immuno-histochemical study using monoclonal antibodies. Circ. Res. 61: 329-336, 1987.

52.   BREITHARDT, G., A. BORGGREFE, A. MARTINEZ-RUBIO, AND T. BUDDE. Pathophysiological mechanisms of ventricular tachyarrhythmias. Eur. Heart J. 10, Suppl. E: 9-18, 1989.

53.   BRILLA, C. G., R. PICK, L. B. TAN, J. S. JANICKI, AND K. T. WEBER. Remodeling of the rat right and left ventricles in experimental hypertension. Circ. Res. 67: 1355-1364, 1990.

54.   BRILLA, C. G., G. ZHOU, L. MATSUBARA, AND K. T. WEBER. Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. J. Mol. Cell. Cardiol. 26: 809-820, 1994.

55.   BRILLANTES, A. M., P. ALLEN, T. TAKAHASHI, S. IZUMO, AND A. R. MARKS. Differences in cardiac calcium release channel (ryanodine receptor) expression in myocardium from patients with end-stage heart failure caused by ischemic versus dilated cardiomyopathy. Circ. Res. 71: 18-26, 1992.

56.   BRISTOW, M. R., R. GINSBURG, W. MINOBE, R. S. CUBICCIOTI, W. S. SAGEMAN, K. LURIE, M. E. BILLINGHAM, D. C. HARRISON, AND E. B. STINSON. Decreased catecholamine sensitivity and beta-adrenergic receptor density in failing human heart. N. Engl. J. Med. 307: 205-211, 1982.

57.   BRISTOW, M. R., R. GINSBURG, V. UMANS, M. FOWLER, W. MINOBE, R. RASMUSSEN, P. ZERA, R. MENLOVE, P. SHAH, S. JAMIESON, AND R. B. SRINSON. 1- and 2-adrenergic-receptor subpopulations in non failing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective 1 receptor down-regulation in heart failure. Circ. Res. 59: 297-309, 1986.

58.   BRISTOW, M. R., W. MINOBE, R. RASMUSSEN, P. LARRABEE, L. SKERI, J. W. KLEIN, F. L. ANDERSON, J. MURRAY, L. MESTRONI, S. V. KARWANDE, M. FOWLER, AND R. GINSBURG. -Adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms. J. Clin. Invest. 89: 803-815, 1992.

59.   BRODDE, O.-E.. 1- and 2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure. Pharmacol. Rev. 43: 203-241, 1991.

60.   BRODDE, O.-E., M. C. MICHEL, AND H.-R. ZERKOWSKI. Signal transduction mechanisms controlling cardiac contractility and their alterations in chronic heart failure. Cardiovasc. Res. 30: 570-584, 1995.

61.   BROOKS, W. W., O. H. L. BING, A. S. BLAUSTEIN, AND P. D. ALLEN. Comparison of contractile state and myosin isozymes of rat right and left ventricular myocardium. J. Mol. Cell. Cardiol. 19: 433-440, 1987.

62.   BRUTSAERT, D. L., AND S. U. SYS. Relaxation and diastole of the heart. Physiol. Rev. 69: 1228-1315, 1989.

63.   CALLENS-EL AMRANI, F., E. MAYOUX, C. MOUAS, R. CLAPIER-VENTURA, D. HENZEL, D. CHARLEMAGNE, AND B. SWYNGHEDAUW. Normal responsiveness to external Ca and to Ca-channel modifying agents in hypertrophied rat heart. Am. J. Physiol. 258 (Heart Circ. Physiol. 27): H1727-H1734, 1990.

64.   CALLENS-EL AMRANI, F., F. PAOLAGGI, AND B. SWYNGHEDAUW. Remodelling of the heart in DOCA-salt hypertensive rats by propranolol and by alpha 2-agonist, rilmenidine. J. Hypertens. 7: 947-954, 1989.

65.   CALLENS-EL AMRANI, F., L. SNOECKX, AND B. SWYNGHEDAUW. Anoxia-induced changes in ventricular diastolic compliance in two models of hypertension in rats. J. Hypertens. 10: 229-236, 1992.

66.   CALLEWAERT, G.. Excitation-contraction coupling in mammalian cardiac cells. Cardiovasc. Res. 26: 923-932, 1992.

67.   CAMERON, J. S., S. KIMURA, D. A. JACKSON-BURNS, D. B. SMITH, AND A. L. BASSETT. ATP-sensitive K⁺ channels are altered in hypertrophied ventricular myocytes. Am. J. Physiol. 255(Heart Circ. Physiol. 24): H1254-H1258, 1988.

68.   CAMPBELL, S. E., A. A. DIAS-ARIAS, AND K. T. WEBER. Fibrosis of the human heart and systemic organs in adrenal adenoma. Blood Pressure 1: 149-156, 1992.

69.   CAPASSO, J. M., A. MALHOTRA, J. SCHEUER, AND E. H. SONNENBLICK. Myocardial, biochemical, contractile and electrical performance following imposition of hypertension in young and old rats. Circ. Res. 58: 445-460, 1986.

70.   CARLYLE, W. C., C. A. TOHER, J. R. VANDERVELDE, K. M. MCDONALD, D. C. HOMANS, AND J. N. COHN. Changes in -actin mRNA expression in remodeling canine myocardium. J. Mol. Cell. Cardiol. 28: 53-63, 1996.

71.   CARRÉ, F., F. RANNOU, C. SAINTE-BEUVE, B. CHEVALIER, J. M. MOALIC, B. SWYNGHEDAUW, AND D. CHARLEMAGNE. Arrhythmogenicity of the hypertrophied and senescent heart and relationship to membrane proteins involved in the altered calcium handling. Cardiovasc. Res. 27: 1784-1789, 1993.

72.   CERBAI, E., M. BARBIERI, Q. LI, AND A. MUGELLI. Ionic basis of action potential prolongation of hypertrophied cardiac myocytes isolated from hypertensive rats of different ages. Cardiovasc. Res. 28: 1180-1187, 1994.

73.   CERBAI, E., M. BARBIERI, AND A. MUGELLI. Characterization of the hyperpolarisation-activated current I_f in ventricular myocytes isolated from hypertensive rats. J. Physiol. (Lond.) 481: 585-591, 1994.

74.   CHALLAH, M., A. NICOLETTI, J.-F. ARNAL, M. PHILIPPE, I. LABOULANDINE, J. ALLEGRINI, F. ALHENC-GELAS, S. DANILOV, AND J.-B. MICHEL. Cardiac angiotensin converting enzyme overproduction indicates interstitial activation in renovascular hypertension. Cardiovasc. Res. 30: 231-239, 1995.

75.   CHAPMAN, D., K. T. WEBER, AND M. EGHBALI. Regulation of fibrillar collagen types I and III and basement membrane type IV collagen gene expression in pressure overloaded rat myocardium. Circ. Res. 67: 787-794, 1990.

76.   CHARLEMAGNE, D., J. M. MAIXENT, M. PRETESEILLE, AND L. G. LELIÈVRE. Ouabain binding sites and (Na⁺,K⁺)-ATPase activity in rat cardiac hypertrophy. Expression of the neonatal forms. J. Biol. Chem. 261: 185-189, 1986.

77.   CHARLEMAGNE, D., J. ORLOWSKI, P. OLIVIERO, F. RANNOU, C. SAINTE-BEUVE, B. SWYNGHEDAUW, AND L. K. LANE. Alteration of (Na⁺,K⁺)-ATPase subunit mRNA and protein levels in hypertrophied heart. J. Biol. Chem. 269: 1541-1547, 1994.

78.   CHENG, W., B. LI, J. KAJSTURA, P. LI, M. S. WOLIN, E. H. SONNENBLICK, T. H. HINTZE, G. OLIVETTI, AND P. ANVERSA. Stretch-induced programmed myocyte cell death. J. Clin. Invest. 96: 2247-2259, 1995.

79.   CHEVALIER, B., I. BERREBI-BERTRAND, L. G. LELIÈVRE, C. MOUAS, AND B. SWYNGHEDAUW. Diminished toxicity of ouabain in hypertrophied rat heart. Pflügers Arch. 414: 311-316, 1989.

80.   CHEVALIER, B., D. HEUDES, C. HEYMES, A. BASSETT, T. DAKHLI, Y. BANSART, S. JOUQUEY, G. HAMON, P. BRUNEVAL, B. SWYNGHEDAUW, AND F. CARRÉ. Trandolapril decreases prevalence of ventricular ectopic activity in middle-aged SHR. Circulation 92: 1947-1953, 1995.

81.   CHEVALIER, B., P. MANSIER, F. CALLENS, AND B. SWYNGHEDAUW. The beta-adrenergic system is modified in compensatory pressure cardiac overload in rats: physiological and biochemical evidence. J. Cardiovasc. Pharmacol. 13: 412-420, 1989.

82.   CHEVALIER, B., P. MANSIER, E. TEIGER, AND F. CALLENS-EL. AMRANI, AND B. SWYNGHEDAUW. Alterations in adrenergic and muscarinic receptors in aged rat heart. Effects of chronic administration of propranolol and atropine. Mech. Ageing Dev. 60: 215-224, 1991.

83.   CHIDSEY, C. A., E. H. SONNENBLICK, A. G. MORROW, AND E. BRAUNWALD. Noreprinephrine stores and contractility force of papillary muscle from the failing heart. Circulation 33: 43-51, 1966.

84.   CHIDSEY, C. A., E. C. WEINBACH, D. E. POOL, AND A. G. MORROW. Biochemical studies of energy production in the failing human heart. J. Clin. Invest. 45: 40-53, 1966.

85.   CHIEN, K. R., H. ZHU, K. U. KNOWLTON, W. MILLER-HANCE, M. VAN BILSEN, T. X. O'BRIEN, AND S. M. EVANS. Transcriptional regulation during cardiac growth and development. Annu. Rev. Physiol. 55: 77-95, 1993.

86.   CLEUTJENS, J. P. M., J. C. KANDALA, R. V. GUNTAKA, AND K. T. WEBER. Regulation of collagen degradation in the rat myocardium after infarction. J. Mol. Cell. Cardiol. 27: 1281-1292, 1995.

87.   CLEUTJENS, J. P. M., M. J. VERLUYTEN, J. F. SMITHS, AND M. J. DAEMENS. Collagen remodeling after myocardial infarction in the rat heart. Am. J. Pathol. 147: 325-338, 1995.

88.   COHEN-SOLAL, A., D. HIMBERT, P. GUÉRET, AND R. GOURGON. Le "remodelage" ventriculaire après infarctus du myocarde. Arch. Mal. Coeur Vaiss. 84: 847-853, 1991.

89.   COHN, J. N. Critical review of heart failure: the role of left ventricular remodeling in the therapeutic response. Clin. Cardiol. 18, Suppl. IV: IV4-IV12, 1995.

90.   COHN, J. N.. Structural basis for heart failure. Ventricular remodeling and its pharmacological inhibition. Circulation 91: 2504-2507, 1995.

91.   COLLINS, J. F., C. PAWLOSKI-DAHM, M. G. DAVIS, N. BALL, G. W. DORN II, AND R. A. WALSH. The role of cytoskeleton in left ventricular pressure overload hypertrophy and failure. J. Mol. Cell. Cardiol. 28: 1435-1443, 1996.

92.   CONRAD, C. H., W. W. BROOKS, J. A. HATES, S. SEN, K. G. ROBINSON, AND O. H. L. BING. Myocardial fibrosis and stiffness with hypertrophy and heart failure in the spontaneously hypertensive rat. Circulation 91: 161-170, 1995.

93.   CONSENSUS TRIAL STUDY GROUP. Effects of enalapril on mortality in severe congestive heart failure. N. Engl. J. Med. 316: 1429-1435, 1987.

94.   CONTARD, F., V. KOTELIANSKY, F. MAROTTE, I. DUBUS, L. RAPPAPORT, AND J.-L. SAMUEL. Specific alterations in the distribution of extracellular matrix components within rat myocardium during the development of pressure overload. Lab. Invest. 64: 65-75, 1991.

95.   COONAR, A. S., AND W. J. MCKENNA. Hypertrophic cardiomyopathy. In: Heart Failure. Scientific Principles and Clinical Practice, edited by P. A. Poole-Wilson, W. S. Colucci, B. M. Massie, K. Chatterjee, and A. J. S. Coats. New York: Churchill Livingstone, 1997, chapt. 27, p. 379-399.

96.   CORDA, S., A. MEBAZAA, M.-P. GANDOLFINI, C. FITTING, F. MAROTTE, J. PEYNET, D. CHARLEMAGNE, J.-M. CAVAILLON, D. PAYEN, L. RAPPAPORT, AND J.-L. SAMUEL. Trophic effect of human pericardial fluid on adult myocytes. Differential role of fibroblast growth factor-2 and factors related to ventricular hypertrophy. Circ. Res. 81: 679-687, 1997.

97.   CORMAN, B., AND J. B. MICHEL. Renin-angiotensin system, converting enzyme inhibition and kidney functionin aging female rats. Am. J. Physiol. 251(Regulatory Integrative Comp. Physiol. 20): R450-R455, 1986.

98.   COULOMBE, A., A. MONTAZA, P. RICHER, B. SWYNGHEDAUW, AND E. CORABOEUF. Reduction of calcium-independent transient outward current density in DOCA-salt hypertrophied rat ventricular myocytes. Pflügers Arch. 427: 47-55, 1994.

99.   CROZATIER, B., AND J. BO. SU, A. CORSIN, AND N. H. BOUANANI. Species differences in myocardial -adrenergic receptor regulation in response to hyperthyroidism. Circ. Res. 69: 1234-1243, 1991.

100.   CRUMB, W. J.. JR., J. D. PIGOTT, AND C. W. CLARKSON. Comparison of I_to in young and adult human atrial myocytes: evidence for developmental changes. Am. J. Physiol. 268(Heart Circ. Physiol. 37): H1335-H1342, 1995.

101.   CUMMINS, P. (Editor). Growth Factors and the Cardiovascular System. Boston: Kluwer, 1993.

102.   CUMMINS, P.. Transitions in human atrial and ventricular myosin light-chain isoenzymes in response to cardiac-pressure-overload-induced hypertrophy. Biochem. J. 205: 195-204, 1982.

103.   D'AGNOLO, M. D., G. B. LUCIANI, A. MAZZUCCO, V. GALLUCCI, AND G. SALVIATI. Contractile properties and Ca²⁺ release activity of the sarcoplasmic reticulum in dilated cardiomyopathy. Circ. Res. 85: 518-525, 1992.

104.   DANNER, D. B., AND N. J. HOLBROOK. Alterations in gene expression with aging. In: Handbook of the Biology of Aging, edited by E. L. Schneider and J. W. Rowe. San Diego: Academic, 1990, chapt. 6, p. 97-115.

105.   DAVIES, C. H., K. DAVIA, J. G. BENNETT, J. R. PEPPER, P. A. POOLE-WILSON, AND S. E. HARDING. Reduced contraction and altered frequency response of isolated ventricular myocytes from patients with heart failure. Circulation 92: 2540-2549, 1995.

106.   DEAL, K. K., S. K. ENGLAND, AND M. M. TAMKUN. Molecular physiology of cardiac potassium channels. Physiol. Rev. 76: 49-67, 1996.

107.   DELCAYRE, C., D. KLUG, N. V. THIEM, C. MOUAS, AND B. SWYNGHEDAUW. Aortic perfusion pressure as early determinant of -isomyosin expression in perfused hearts. Am. J. Physiol. 263(Heart Circ. Physiol. 32): H1537-H1545, 1992.

108.   DELCAYRE, C., J.-L. SAMUEL, F. MAROTTE, M. BEST-BELPOMME, AND L. RAPPAPORT. Synthesis of stress proteins is transiently increased in rat cardiac myocytes 2-4 days after imposition of hemodynamic overload. J. Clin. Invest. 82: 460-468, 1988.

109.   DELL'ITALIA, L. J., Q. C. MENG, E. BALCELLS, C.-C. WEI, R. PALMER, G. R. HAGEMAN, J. DURAND, G. H. HANKES, AND S. OPARIL. Compartmentalization of angiotensin II generation in the dog heart. Evidence for independent mechanisms in intravascular and interstitial spaces. J. Clin. Invest. 100: 253-258, 1997.

110.   DELL'ITALIA, L. J., AND S. OPARIL. Cardiac renin angiotensin system in hypertrophy and the progression to heart failure. Heart Failure Rev. 1: 63-72, 1996.

111.   DERISI, J. L., V. R. IYER, AND P. O. BROWN. Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278: 680-686, 1997.

112.   DIEZ, J., C. LAVIADES, G. MAYOR, M. J. GIL, AND I. MONREAL. Increased serum concentrations of procollagen peptides in essential hypertension. Relation to cardiac alterations. Circulation 91: 1450-1456, 1995.

113.   DIXON, I. M., T. HATA, AND N. S. DHALLA. Sarcolemmal Na⁺-K⁺ ATPase activity in congestive heart failure due to myocardial infarction. Am. J. Physiol. 262(Cell Physiol. 31): C664-C671, 1992.

114.   DIXON, I. M., T. HATA, AND N. S. DHALLA. Sarcolemmal calcium transport in congestive heart failure due to myocardial infarction in rats. Am. J. Physiol. 262(Heart Circ. Physiol. 31): H1387-H1394, 1992.

115.   DORN, G. W., J. ROBBINS, N. BALL, AND R. A. WALSH. Myosin heavy chain regulation and myocyte contractile depression after LV hypertrophy in aortic-banded mice. Am. J. Physiol. 267(Heart Circ. Physiol. 36): H400-H405, 1994.

116.   DOWNING, S. E., AND V. CHEN. Myocardial injury following endogenous catecholamine release in rabbits. J. Mol. Cell. Cardiol. 17: 377-387, 1985.

117.   DREXLER, H., J. HANZE, M. FINCKH, W. LU, H. JUST, AND R. E. LANG. Atrial natriuretic peptide in a rat model of cardiac failure: atrial and ventricular mRNA, atrial content, plasma levels, and effect of volume loading. Circulation 79: 620-633, 1989.

118.   DREXLER, H., D. HAYOZ, T. MUNZEL, B. HORNIG, H. JUST, H. R. BRUNNER, AND R. ZELIS. Endothelial function in chronic congestive heart failure. Am. J. Cardiol. 69: 1596-1601, 1992.

119.   DRITSAS, A., E. SBAROUNI, D. GILLIGAN, P. NIHOYANNOPOULOS, AND C. M. OAKLEY. QT-interval abnormalities in hypertrophic cardiomyopathy. Clin. Cardiol. 15: 739-742, 1992.

120.   DZAU, V. J.. Cardiac renin-angiotensin system: molecular and functional aspect. Am. J. Med. 84: 22-27, 1988.

121.   DZAU, V. J., M. PACKER, L. S. LILLY, S. L. SWARTZ, N. K. HOLLEBERG, AND G. H. WILLIAMS. Prostaglandins in severe congestive heart failure. N. Engl. J. Med. 310: 347-352, 1984.

122.   EGHBALI, M., M. EGHBALI, T. F. ROBINSON, S. SEIFTER, AND O. O. BLUMENFELD. Collagen accumulation in heart ventricles as a function of growth and aging. Cardiovasc. Res. 23: 723-729, 1989.

123.   EICHBORN, E. J., AND M. R. BRISTOW. Medical therapy can improve the biological properties of the chronically failing heart. A new era in the treatment of heart failure. Circulation 94: 2285-2296, 1996.

124.   ESCHENHAGEN, T., U. MENDE, M. DIEDERICH, B. HERTLE, C. MEMMESHEIMER, A. POHL, W. SCHMITZ, H. SCHOLZ, M. STEINFATH, M. BÖHM, M. C. MICHEL, O.-E. BRODDE, AND A. RAAP. Chronic treatment with carbachol sensitizes the myocardium to cAMP-induced arrhythmia. Circulation 93: 763-771, 1996.

125.   ESCHENHAGEN, T., U. MENDE, M. NOSE, W. SCHMITZ, H. SCHOLZ, A. HAVERICH, S. HIRT, V. DÖRING, P. KALMAR, W. HÖPPNER, AND H.-J. SEITZ. Increased messenger RNA level of the inhibitory G protein -SUBUNIT G_i-2 in human end-stage heart failure. Circ. Res. 70: 688-696, 1992.

126.   ESCHENHAGEN, T., U. MENDE, M. NOSE, W. SCHMITZ, H. SCHOLZ, A. WARNHOLTZ, AND J.-M., WÜSTEL. Isoprenaline-induced increase in mRNA levels of inhibitory G-protein -subunit in rat heart. Naunyn-Schmiedebergs Arch. Pharmacol. 343: 609-615, 1991.

127.   ESPINASSE, I., V. IOURGENKO, C. RICHER, M. HEIMBURGER, N. DEFER, E. PUSSARD, J.-F. GIUDICELLI, J.-B. MICHEL, AND J.-J. MERCADIER. Decreased type VI, but not type V, adenylyl cyclase mRNA isoform expression in the left ventricle of rats with myocardial infarction and heart failure (Abstract). J. Am. Coll. Cardiol. 29, Suppl. A: 231A, 1997.

128.   EVERETT, A. D., A. TUFRO-MCREDDIE, A. FISHER, AND R. A. GOMEZ. Angiotensin receptor regulates cardiac hypertrophy and transforming growth factor-1 expression. Hypertension 23: 587-592, 1994.

129.   FABIATO, A., AND F. FABIATO. Calcium-induced release of calcium from the sarcoplasmic reticulum of skinned cells from adult human, dog, cat, rabbit, rat, and frog hearts and from fetal and newborn rat ventricles. Ann. NY Acad. Sci. USA 307: 491-522, 1978.

130.   FARHADIAN, F., A. BARRIEUX, S. LORTET, F. MAROTTE, P. OLIVIERO, L. RAPPAPORT, AND J.-L. SAMUEL. Differential splicing of fibronectin pre-messenger ribonucleic acid during cardiac ontogeny and development of hypertrophy in the rat. Lab. Invest. 71: 552-559, 1994.

131.   FARHADIAN, F., F. CONTARD, A. SABRI, J.-L. SAMUEL, AND L. RAPPAPORT. Fibronectin and basement membrane in cardiovascular organogenesis and disease pathogenesis. Cardiovasc. Res. 32: 433-442, 1996.

132.   FELDMAN, A. M., A. E. CATES, W. B. VEAZEY, R. E. HERSHBERGER, M. R. BRISTOW, K. L. BAUGHMAN, W. A. BAUMGARTNER, AND C. VAN DOP. Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart. J. Clin. Invest. 82: 189-197, 1988.

133.   FELDMAN, M. D., L. CEPLAS, J. K. GWATHMEY, P. PHILIPS, S. E. WARREN, F. J. SCHOEN, W. GROSSMAN, AND J. P. MORGAN. Deficient production of cAMP: pharmacological evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation 75: 331-339, 1987.

134.   FELDMAN, A., P. E. RAY, C. M. SILAN, J. A. MERCER, W. MINOBE, AND M. R. BRISTOW. Selective gene expression in failing human heart. Quantification of steady-state levels of messenger RNA in endomyocardial biopsies using the polymerase chain reaction. Circulation 83: 1866-1872, 1991.

135.   FELDMAN, A., E. O. WEINBERG, P. E. RAY, AND B. H. LORELL. Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation in rats with chronic aortic banding. Circ. Res. 73: 184-192, 1993.

136.   FERRARI, R., T. BACHETTI, R. CONFORTINI, C. OPASICH, O. FEBO, A. CORTI, G. CASSANI, AND O. VISIOLI. Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Circulation 92: 1479-1486, 1995.

137.   FISCHER, J. E., W. D. HORST, AND I. J. KOPIN. Norepinephrine metabolism in hypertrophied rat heart. Nature 207: 951-953, 1965.

138.   FLEG, J. L.. Alterations in cardiovascular structure and function with advancing age. Am. J. Cardiol. 57: 33C-44C, 1986.

139.   FLIEGEL, L., AND J. R. B. DYCK. Molecular biology of the cardiac sodium/hydrogen exchanger. Cardiovasc. Res. 29: 155-159, 1995.

140.   FOLKOW, B., AND A. SVANBORG. Physiology of cardiovascular aging. Physiol. Rev. 73: 725-764, 1993.

141.   FRANCH, H. A., R. A. F. DIXON, E. H. BLAINE, AND P. K. S. SIEGL. Ventricular atrial natriuretic factor in the cardiomyopathic hamster model of congestive heart failure. Circ. Res. 62: 31-36, 1988.

142.   FRANCIS, G. S., S. R. GOLDSMITH, T. B. LEVINE, M. T. OLIVARI, AND J. N. COHN. The neuro-humoral axis in congestive heart failure. Ann. Intern. Med. 101: 370-377, 1984.

143.   FRANZ, M. R.. Mechanical-electrical feed-back in ventricular myocardium. Cardiovasc. Res. 32: 15-24, 1996.

144.   FU, L.-X., Q.-P. FENG, Q.-M. LIANG, X.-Y. SUN, T. HEDNER, J. HOEBEKE, AND A. HJALMARSON. Hypersensitivity of G_i protein mediated muscarinic receptor adenylyl cyclase in chronic ischaemic heart failure in the rat. Cardiovasc. Res. 27: 2065-2070, 1993.

145.   FULLERTON, M. J., AND J. W. FUNDER. Aldosterone and cardiac fibrosis: in vitro studies. Cardiovasc. Res. 28: 1863-1867, 1994.

146.   GAASCH, W. H., C. S. APSTEIN, AND H. J. LEVINE. Diastolic properties of the left ventricle. In: The Ventricle: Basic and Clinical Aspect, edited by H. J. Levine and W. H. Gaasch. Boston: Martinus Nijhoff, 1985, p. 143.

147.   GANGULY, P. K., AND G. R. SHERWOOD. Noradrenaline turnover and metabolism in myocardium following aortic constriction in rats. Cardiovasc. Res. 25: 579-585, 1991.

148.   GAUDRON, P., C. EILLES, I. KUGLER, AND G. ERTL. Progressive left ventricular dysfunction and remodeling after myocardial infarction. Potential mechanisms and early predictors. Circulation 87: 755-763, 1993.

149.   GAUTIER, C., G. TAVERNIER, F. CHARPENTIER, D. LANGIN, AND H. LE MAREC. Functional ₃-adrenoceptor in the human heart. J. Clin. Invest. 98: 556-562, 1996.

150.   GAVRAS, H., J. J. BROWN, A. F. LEVER, R. F. MACADAM, AND J. I. S. ROBERTSON. Acute renal failure, tubular necrosis, and myocardial infarction induced in the rabbit by intravenous angiotensin II. Lancet 2: 19-22, 1971.

151.   GELBAND, H., AND A. L. BASSETT. Depressed transmembrane potentials during experimentally induced ventricular failure in cats. Circ. Res. 32: 625-634, 1973.

152.   GERDES, A. M., AND J. M. CAPASSO. Structural remodeling and mechanical dysfunction of cardiac myocytes in heart failure. J. Mol. Cell. Biol. 27: 849-856, 1995.

153.   GIBBS, C. L., AND J. B. CHAPMAN. Cardiac mechanics and energetics: chemomechanical transduction in cardiac muscle. Am. J. Physiol. 249(Heart Circ. Physiol. 18): H199-H206, 1985.

154.   GIDH-JAIN, M., B. HUANG, P. JAIN, V. BATTULA, AND N. EL-SHERIF. Reemergence of the foetal pattern of L-type calcium channel gene expression in noninfarcted myocardium during left ventricular remodeling. Biochem. Biophys. Res. Commun. 216: 892-897, 1995.

155.   GIDH-JAIN, M., B. HUANG, P. JAIN, AND N. EL-SHERIF. Differential expression of voltage-gated K⁺ channel genes in left ventricular remodeled myocardium after experimental myocardial infarction. Circ. Res. 79: 669-675, 1996.

156.   GIORDANO, F. J., H. HE, P. MCDONOUGH, M. MEYER, M. R. SAYEN, AND W. H. DILLMANN. Adenovirus-mediated gene transfer reconstitutes depressed sarcoplasmic reticulum Ca²⁺-ATPase levels and shortens prolonged cardiac myocyte Ca²⁺ transients. Circulation 96: 400-403, 1997.

157.   GO, L. O., M. C. MOSCHELLA, J. WATRAS, K. K. HANDA, B. S. FYFE, AND A. R. MARKS. Differential regulation of two types of intracellular calcium release channels during end-stage heart failure. J. Clin. Invest. 95: 888-894, 1995.

158.   GOLDSPINK, G. Biochemical energetics for fast and slow muscles. In: Comparative Physiology. Functional Aspects of Structural Materials, edited by L. Bolis, H. P. Maddrell, and K. Schmidt-Nielsen. Amsterdam: North-Holland, 1975, p. 173-185.

159.   GOLDSTEIN, S., V. G. SHAROV, J. M. COOK, AND H. N. SABBAH. Ventricular remodeling: insights from pharmacologic interventions with angiotensin-converting enzyme inhibitors. Mol. Cell. Biochem. 147: 51-55, 1995.

160.   GOMEZ, A. M., H. H. VALVIDIA, H. CHENG, M. R. LEDERER, L. F. SANTANA, M. B. CANNELL, S. A. MCCUNE, R. A. ALTSCHULD, AND W. J. LEDERER. Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science 276: 800-806, 1997.

161.   GOTTLIEB, R. A., K. O. BURLESON, R. A. KLONER, B. M. BABLOR, AND R. L. ENGLER. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J. Clin. Invest. 94: 1621-1628, 1994.

162.   GRAJEK, S., M. LESIAK, M. PYDA, M. ZAJAC, S. PARADOWSKI, AND E. KACZMAREK. Hypertrophy or hyperplasia in cardiac muscle. Post-mortem human morphometric analysis. Eur. Heart J. 14: 40-47, 1993.

163.   GROVE, D., R. ZAK, K. G. NAIR, AND V. ASCHENBRENNER. Biochemical correlates of cardiac hypertrophy. IV. Observations on the cellular organization of growth during myocardial hypertrophy in the rat. Circ. Res. 25: 473-485, 1969.

164.   GRUVER, C. L., F. DEMAYO, M. A. GOLDSTEIN, AND A. R. MEANS. Targeted developmental overexpression of calmodulin induces proliferative and hypertrophic growth of cardiomyocytes in transgenic mice. Endocrinology 133: 376-388, 1993.

165.   GUARDA, E., L. C. KATWA, P. R. MYERS, S. C. TYAGI, AND K. T. WEBER. Effects of endothelins on collagen turn-over in cardiac fibroblasts. Cardiovasc. Res. 27: 2130-2134, 1993.

166.   GUARNIERI, T., C. R. FILBAUM, G. ZITNIK, G. ROTH, AND E. G. LAKATTA. Contractile and biochemical correlates of -adrenergic stimulation of the aged heart. Am. J. Physiol. 239(Heart Circ. Physiol. 8): H501-H508, 1980.

167.   GÜLCH, R. W.. The effects of elevated chronic loading on the action potential of mammalian myocardium. J. Mol. Cell. Cardiol. 12: 415-420, 1980.

168.   GUNTESKI-HAMBLIN, A.-M., G. SONG, R. A. WALSH, M. FRENSKE, G. P. BOIVIN, G. W. DORN II, M. L. KAETZEL, N. D. HORSEMAN, AND J. R. DEDMAN. Annexin VI overexpression targeted to heart alters cardiomyocyte function in transgenic mice. Am. J. Physiol. 270 (Heart Circ. Physiol. 39): H1091-H1100, 1996.

169.   GWATHMEY, J. K., L. COPELAS, R. MACKINNON, M. D. SCHOEN, W. FELDMAN, W. GROSSMAN, AND J. P. MORGAN. Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ. Res. 61: 70-76, 1987.

170.   GWATHMEY, J. K., AND J. P. MORGAN. Altered calcium handling in experimental pressure-overload hypertrophy in the ferret. Circ. Res. 57: 836-843, 1985.

171.   GWATHMEY, J. K., M. T. SLAWSKY, R. J. HAIJAR, G. M. BRIGGS, AND J. P. MORGAN. Role of the intracellular calcium handling in force-interval relationships of human ventricular myocardium. J. Clin. Invest. 85: 1599-1613, 1990.

172.   GWATHMEY, J. K., S. E. WARREN, G. M. BRIGGS, L. COPELAS, M. D. FELDMAN, P. J. PHILIPS, AND M. CALLHAN. JR., F. J. SCHOEN, W. GROSSMAN, AND J. P. MORGAN. Diastolic dysfunction in hypertrophic cardiomyopathy. Effect on active force generation during systole. J. Clin. Invest. 87: 1023-1031, 1991.

173.   HABIB, F., D. DUTKA, D. CROSSMAN, C. M. OAKLEY, AND J. G. CLELAND. Enhanced basal nitric oxide production in heart failure: another failed counterregulatory vasodilator mechanism? Lancet 344: 371-373, 1994.

174.   HALLER, B. G., H. ZUST, S. SHAW, M. P. GNADINGER, D. E. VEHLINGER, AND P. WEIDMANN. Effects of posture and aging on circulating atrial natriuretic peptide levels in man. Hypertension 5: 551-556, 1987.

175.   HAMET, P., L. RICHARD, T. V. DAM, E. TEIGER, S. N. ORLOV, L. GABOURY, F. GOSSARD, AND J. TREMBLAY. Apoptosis in target organs of hypertension. Hypertension 26: 642-648, 1995.

176.   HANF, R., I. DURUBAIX, AND L. LELIEVRE. Rat cardiac hypertrophy: altered sodium-calcium exchange activity in sarcolemmal vesicles. FEBS Lett. 236: 145-149, 1988.

177.   HANO, O., K. Y. BOGDANOV, M. SAKAI, R. G. DANZIGER, H. A. SPURGEON, AND E. G. LAKATTA. Reduced threshold for myocardial cell calcium intolerance in the rat with aging. Am. J. Physiol. 269(Heart Circ. Physiol. 38): H1607-H1612, 1995.

178.   HANO, O., AND E. G. LAKATTA. Diminished tolerance of prehypertrophic, cardiomyopathic Syrian hamster hearts to Ca²⁺ stresses. Circ. Res. 69: 123-133, 1991.

179.   HARDOUIN, S., F. BOURGEOIS, S. BESSE, C. A. MACHIDA, B. SWYNGHEDAUW, AND J. M. MOALIC. Decreased accumulation of 1-adrenergic receptor, G_s and total myosin heavy chain messenger RNAs in the left ventricle of senescent rat heart. Mech. Ageing Dev. 71: 169-188, 1993.

180.   HARDOUIN, S., P. MANSIER, B. BERTIN, T. DAKHLY, B. SWYNGHEDAUW, AND J.-M. MOALIC. -Adrenergic and muscarinic receptor expression are regulated in opposite ways during senescence in rat left ventricle. J. Mol. Cell. Cardiol. 29: 309-319, 1997.

181.   HART, G.. Cellular electrophysiology in cardiac hypertrophy and failure. Cardiovasc. Res. 28: 933-946, 1994.

182.   HASENFUSS, G., C. HOLUBARSCH, H.-P. HERMANN, K. ASTHEIMER, B. PIESKE, AND H. JUST. Influence of the force-frequency relationship on the haemodynamic and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy. Eur. Heart J. 15: 164-170, 1994.

183.   HASENFUSS, G., C. HOLUBARSCH, H. JUST, AND N. R. ALPERT (Editors). Cellular and Molecular Alterations in the Failing Human Heart. Darmstadt: Springer-Verlag, 1992.

184.   HASENFUSS, G., L. A. MULIERI, B. J. LEAVITT, P. D. ALLEN, J. R. HAEBERLE, AND N. R. ALPERT. Alteration in contractile function and excitation-contraction coupling in dilated cardiomyopathy. Circ. Res. 70: 1225-1232, 1992.

185.   HASHIMOTO, K., M. HIROSE, S. FURUKAWA, H. HAYAKAWA, AND E. KIMURA. Changes in hemodynamics and bradykinin concentration in coronary sinus blood in experimental coronary artery occlusion. Jpn. Heart J. 18: 679-689, 1977.

186.   HATEM, S. N., J. S. K. SHAM, AND M. MORAD. Enhanced Na⁺-Ca²⁺ exchange activity in cardiomyopathic Syrian hamster. Circ. Res. 74: 253-261, 1994.

187.   HATT, P. Y. Experimental models. In: Cardiac Failure, edited by B. Swynghedauw. Paris: INSERM, 1990, chapt. 2, p. 9-22.

188.   HATT, P. Y., G. BERJAL, J. MORAVEC, AND B. SWYNGHEDAUW. Heart failure: an electron microscopic study of the left ventricular papillary muscle in aortic insufficiency in the rabbit. J. Mol. Cell. Cardiol. 1: 235-237, 1970.

189.   HATT, P. Y., C. LEDOUX, AND J. P. BONVALET. Lyse et sunthèse des protéines myocardiques au cours de l'insuffisance cardiaque expérimentale. Arch. Mal. Coeur Vaiss. 12: 1703-1721, 1965.

190.   HATT, P. Y., K. RAKUSAN, P. GASTINEAU, AND M. LAPLACE. Morphometry and ultrastructure of heart hypertrophy induced by chronic volume overload (aorta-cava fitula in the rat). J. Mol. Cell. Cardiol. 11: 989-998, 1979.

191.   HAYASHI, H., AND S. SHIBATA. Electrical properties of cardiac cell membrane of spontaneously hypertensive rats. Eur. J. Pharmacol. 27: 255-259, 1974.

192.   HAYWOOD, G. A., L. GULLESTAD, T. KATSUYA, H. G. HUTCHINSON, R. E. PRATT, M. HORIUCHI, AND M. B. FOWLER. AT₁ and AT₂ angiotensin receptor gene expression in human heart failure. Circulation 95: 1201-1206, 1997.

193.   HAYWOOD, G. A., P. S. TSAO, H. E. VON DER LEYEN, M. J. MANN, P. J. KEELING, P. T. TRINDDADE, N. P. LEWIS, C. D. BYRNE, P. R. RICKENBACHER, N. H. BISHOPRIC, J. P. COOKE, W. J. MCKENNA, AND M. B. FOWLER. Expression of inducible nitric oxide synthase in human heart failure. Circulation 93: 1087-1094, 1996.

194.   HENDERSON, A. H., R. J. CRAIG, E. H. SONNENBLICK, AND C. W. URSCHEL. Species differences in intrinsic myocardial contractility. Proc. Soc. Exp. Biol. Med. 134: 939-932, 1970.

195.   HENEGAR, J. R., G. L. BROWER, H. KABOUR, AND J. S. JANICKI. Catecholamine reponse to chronic ANG II infusion and its role in myocyte and coronary vascular damage. Am. J. Physiol. 269(Heart Circ. Physiol. 38): H1564-H1569, 1995.

196.   HENKEL, R. D., J. L. VANDEBERG, R. E. SHADE, J. J. LÉGER, AND R. A. WALSH. Cardiac -myosin heavy chain diversity in normal and chronically hypertensive baboons. J. Clin. Invest. 83: 1487-1493, 1989.

197.   HEWETT, T. E., I. L. GRUPP, G. GRUPP, AND J. ROBBINS. -Skeletal actin is associated with increased contractility in the mouse heart. Circ. Res. 74: 740-746, 1994.

198.   HEYLIGER, C. E., A. R. PRAKASH, AND J. H. MCNEILL. Alterations in membrane Na⁺-Ca²⁺ exchange in the aging myocardium. Age 11: 1-6, 1988.

199.   HEYMES, C., B. SWYNGHEDAUW, AND B. CHEVALIER. Activation of angiotensinogen and angiotensin converting enzyme gene expression in the left ventricle of senescent rats. Circulation 90: 1328-1333, 1994.

200.   HEYMES, C., J.-S. SILVESTRE, C. LLORENS-CORTES, B. CHEVALIER, F. MAROTTE, B. I. LEVY, B. SWYNGHEDAUW, AND J.-L. SAMUEL. Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes. Endocrinology. 139: 2579-2587, 1998.

201.   HIETER, P., AND M. BOGUSKI. Functional genomics: it's all how you read it. Science 278: 601-602, 1997.

202.   HINGLAIS, N., D. HEUDES, A. NICOLETTI, C. NAUDET, M. LAURENT, J. BARIETY, AND J.-B. MICHEL. Co-localization of myocardial fibrosis and inflammatory cells in rats. Lab. Invest. 70: 286-294, 1994.

203.   HIROTA, H., K. YOSHIDA, T. KISHIMOTO, AND T. TAGA. Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc. Natl. Acad. Sci. USA 92: 4862-4866, 1995.

204.   HIRSCH, A. T., C. E. TALSNESS, H. SCHUNKERT, M. PAUL, AND V. J. DZAU. Tissue-specific activation of cardiac angiotensin converting enzyme in experimental heart failure. Circ. Res. 69: 475-482, 1991.

205.   HIRZEL, H., C. TUCHSMID, J. SNEIDER, H. KRAYENBUEHL, AND M. SCHAUB. Relationship between myosin isoenzyme composition, hemodynamics and myocardial structure in various forms of human cardiac hypertrophy. Circ. Res. 57: 729-74O, 1985.

206.   HOH, J. F. Y., G. H. ROSSMANITH, L. J. KWAN, AND A. M. HAMILTON. Adrenaline increases the rate of cycling of crossbridges in rat cardiac muscle as measured by pseudo-random binary noise-modulated perturbation analysis. Circ. Res. 62: 452-461, 1988.

207.   HUANG, H., J. F. ARNAL, C. LLORENS-CORTES, M. CHALLAH, F. ALHENC-GELAS, P. CORVOL, AND P. MICHEL. Discrepancy between plasma and lung angiotensin-converting enzyme activity in experimental congestive heart failure. A novel aspect of endothelium dysfunction. Circ. Res. 75: 454-461, 1994.

208.   HUTCHINS, G. M., AND B. H. BULKLEY. Infarct expansion versus extension: two different complications of acute myocardial infarction. Am. J. Cardiol. 41: 1127-1132, 1978.

209.   HWANG, D. M., A. A. DEMPSEY, R. X. WANG, M. REZVANI, D. BARRANS, K.-S. DAI, H.-Y. WANG, H. MA, E. CUKERMAN, Y.-Q. LIU, J.-R. GU, J.-H. ZHANG, S. K. W. TSUI, M. M. Y. WAYE, K.-P. FUNG, C.-Y. LEE, AND C. C. LIEW. A genome-based resource for molecular cardiovascular medicine: toward a compendium of cardiovascular genes. Circulation 96: 4146-4203, 1997.

210.   IIMOTO, D. S., J. W. COVELL, AND E. HARPER. Increase in cross linking of type I and type III collagen associated with volume overload hypertrophy. Circ. Res. 63: 399-408, 1988.

211.   INGWALL, J. S., J. FRIEDRICH, AND L. NASCIMBEN. Does decreased energy supply contribute to heart failure? The role of the creatine kinase system. In: Heart Hypertrophy and Failure, edited by N. S. Dhalla, G. N. Pierce, V. Panagia, and R. E. Beamish. Boston, MA: Kluwer, 1995, p. 231-239.

212.   INGWALL, J. S., M. F. KRAMER, M. A. FIFER, B. H. LORELL, R. SHEMIN, W. GROSSMAN, AND P. D. ALLEN. The creatine kinase system in normal and diseased human myocardium. N. Engl. J. Med. 313: 1050-1054, 1985.

213.   INOKO, M., Y. KIHARA, I. MORII, H. FUJIWARA, AND S. SASAYAMA. Transition from compensatory hypertrophy to dilated failing left ventricles in Dahl salt-sensitive rats. Am. J. Physiol. 267(Heart Circ. Physiol. 36): H2471-H282, 1994.

214.   ISHIBASHI, Y., H. TSUTSUI, S. YAMAMOTO, M. TAKAHASHI, K. IMANAKA-YOSHIDA, T. YOSHIDA, Y. URABE, M. SUGIMACHI, AND A. TAKESHITA. Role of microtubules in myocyte contractile dysfunction during cardiac hypertrophy in the rat. Am. J. Physiol. 271(Heart Circ. Physiol. 40): H1978-H1987, 1996.

215.   ISOYAMA, S., J. Y. WEI, S. IZUMO, P. FORT, F. J. SCHOEN, AND W. GROSSMAN. Effect of age on the development of cardiac hypertrophy produced by aortic constriction in the rat. Circ. Res. 61: 337-345, 1987.

216.   ITO, Y., J. SUKO, AND C. A. CHIDSEY. Intracellular calcium and myocardial contractility. V. Calcium uptake of sarcoplasmic reticulum fractions in hypertrophied and failing rabbit hearts. J. Mol. Cell. Cardiol. 6: 237-247, 1974.

217.   IWAI, N., H. SHIMOIKE, AND M. KINOSHITA. Cardiac renin-angiotensin system in the hypertrophied heart. Circulation 92: 2690-2696, 1995.

218.   JALIL, J. E., C. W. DOERING, J. S. JANICKI, R. PICK, S. G. SHROFF, AND K. T. WEBER. Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ. Res. 64: 1041-1050, 1989.

219.   JALIL, J. E., J. S. JANICKI, R. PICK, C. ABRAHAMS, AND K. T. WEBER. Fibrosis-induced reduction of endomyocardium in the rat after isoproterenol treatment. Circ. Res. 65: 258-264, 1989.

220.   JAMES, T. N.. Normal and abnormal consequences of apoptosis in the human heart. From postnatal morphogenesis to paroxysmal arrhythmias. Circulation 90: 556-573, 1994.

221.   JANSE, M. J., AND A. L. WIT. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol. Rev. 69: 1049-1169, 1989.

222.   JECK, C. D., R. ZIMMERMANN, J. SCHAPER, AND W. SCHAPER. Decreased expression of calmodulin mRNA in human end stage-heart failure. J. Mol. Cell. Cardiol. 26: 99-107, 1994.

223.   KÄÄB, S., B. NUSS, N. CHIAMVIMPNVAT, B. O'ROURKE, P. H. PAK, D. A. KASS, E. MARBAN, AND G. F. TOMASELLI. Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ. Res. 78: 262-273, 1996.

224.   KADAMBI, V. J., S. PONNIAH, J. M. HARRER, B. D. HOIT, G. W. DORN, R. A. WALSH, AND E. G. KRANIAS. Cardiac-specific overexpression of phospholamban alters calcium kinetics and resultant cardiomyocyte mechanics in transgenic mice. J. Clin. Invest. 97: 533-539, 1996.

225.   KAGAYA, Y., Y. KANNO, D. TAKEYAMA, N. ISHIDE, Y. MARUYAMA, T. TAKAHASHI, T. IDO, AND T. TAKISHIMA. Effects of long-term pressure overload on regional myocardial glucose and free fatty acid uptake in rats. A quantitative autoradiographic study. Circulation 81: 1353-1361, 1990.

226.   KAJSTURA, J., W. CHENG, K. REISS, W. A. CLARK, E. H. SONNENBLICK, S. KRAJEWSKI, J. C. REED, G. OLIVETTI, AND P. ANVERSA. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab. Invest. 74: 86-107, 1996.

227.   KAJSTURA, J., W. CHENG, R. SARANGARAJAN, P. LI, B. LI, J. A. NITAHARA, S. CHAPNICK, K. REISS, G. OLIVETTI, AND P. ANVERSA. Necrotic and apoptotic myocyte cell death in the aging heart of Fischer 344 rats. Am. J. Physiol. 271(Heart Circ. Physiol. 40): H1215-H1228, 1996.

228.   KAJSTURA, J., M. MANSHUKANI, C. WEI, K. REISS, S. KRAJEWSKI, J. C. REED, F. QUAINI, E. H. SONNENBLICK, AND P. ANVERSA. Programmed cell death and expression of the protoncogene BCL-2 in myocytes during post-natal maturation of the heart. Exp. Cell Res. 219: 110-121, 1995.

229.   KATZ, A. M.. Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure. N. Engl. J. Med. 322: 100-110, 1990.

230.   KAWAGUCHI, H., AND A. KITABATAKE. Renin-angiotensin system in failing heart. J. Mol. Cell. Cardiol. 27: 201-209, 1995.

231.   KIM, D. H., F. MKPARU, C. R. KIM, AND R. F. CAROLL. Alterations of Ca²⁺ release channel function in sarcoplasmic reticulum of pressure-overload-induced hypertrophic rat heart. J. Mol. Cell. Cardiol. 26: 1505-1512, 1994.

232.   KISS, E., N. A. BALL, E. G. KRANIAS, AND R. A. WALSH. Differential changes in cardiac phospholamban and sarcoplasmic reticular Ca²⁺-ATPase protein levels. Circ. Res. 77: 759-764, 1995.

233.   KLEIMAN, R. B., AND S. R. HOUSER. Outward currents in normal and hypertrophied feline ventricular myocytes. Am. J. Physiol. 256(Heart Circ. Physiol. 25): H1450-H1461, 1989.

234.   KLUG, D., V. ROBERT, AND B. SWYNGHEDAUW. Role of mechanical and hormonal factors in cardiac remodeling and the biological limits of myocardial adaptation. Am. J. Cardiol. 71: 46A-54A, 1993.

235.   KNOWLTON, A. A., C. M. CONNELLY, M. R. GABRIEL, W. MAMUYAMA, C. S. APSTEIN, AND P. BRECHER. Rapid expression of fibronectin in the rabbit after myocardial infarction with and without reperfusion. J. Clin. Invest. 89: 1060-1068, 1992.

236.   KOCH, W. J., H. A. ROCKMAN, P. SAMAMA, R. A. HAMILTON, R. A. BOUND, C. A. MILANO, AND R. J. LEFKOWITZ. Cardiac function in mice overexpressing the -adrenergic receptor kinase or -ARK inhibitor. Science 268: 1350-1353, 1995.

237.   KOHYA, T., H. YOKOSHIKI, N. TOHSE, M. KANNO, H. NAKAYA, H. SAITO, AND A. KITABATAKE. Regression of left ventricular hypertrophy prevents ischemia-induced lethal arrhythmias. Beneficial effect of angiotensin II blockade. Circ. Res. 76: 892-899, 1995.

238.   KÖHLER, E., S. BERTSCHIN, T. WOODTLI, T. RESINK, AND P. ERNE. Does aldosterone-induced cardiac fibrosis involve direct effects on cardiac fibroblasts? J. Vasc. Res. 33: 315-326, 1996.

239.   KOMURO, I., M. KURABAYASHI, F. SHIBAZAKI, F. TAKAKU, AND Y. YAZAKI. Molecular cloning and characterization of a Ca²⁺-Mg²⁺ dependent adenosine triphosphatase from rat cardiac sarcoplasmic reticulum. J. Clin. Invest. 83: 1102-1108, 1989.

240.   KORYTKOWSKI, M. T., AND P. W. LANDENSON. Age-dependent changes in basal and sodium stimulated atrial and plasma atrial natriuretic factor (ANF) in the rat. J. Gerontol. 46: 107-110, 1991.

241.   KUBOTA, T., C. F. MCTIERNAN, C. S. FRYE, A. J. DEMETRIS, AND A. M. FELDMAN. Cardiac-specific overexpression of tumor necrosis factor-alpha causes lethal myocarditis in transgenic mice. J. Cardiac Failure 3: 117-124, 1997.

242.   LAB, M. J.. Contraction-excitation feed-back in myocardium. Physiological basis and clinical relevance. Circ. Res. 50: 757-766, 1982.

243.   LABEIT, S., B. KOLMERER, AND W. A. LINKE. The giant protein titin. Emerging roles in physiology and pathophysiology. Circ. Res. 80: 290-294, 1997.

244.   LAKATTA, E.. Cardiovascular regulatory mechanisms in advanced age. Physiol. Rev. 73: 413-467, 1993.

245.   LAUER, B., N. V. THIEM, AND B. SWYNGHEDAUW. ATPase activity of the cross-linked complex between cardiac myosin subfragment 1 and actin in several models of chronic overloading. Circ. Res. 64: 1106-1115, 1989.

246.   LECARPENTIER, Y., L. B. BUGAISKY, D. CHEMLA, J. J. MERCADIER, K. SCHWARTZ, R. G. WHALEN, AND J. L. MARTIN. Coordinated changes in myocardial contractility, energetics and myosin isozyme pattern following thoracic aortic stenosis in the young rat. Am. J. Physiol. 252(Heart Circ. Physiol. 21): H275-H282, 1987.

247.   LECARPENTIER, Y., A. WALDENSTROM, M. CLERGUE, D. CHEMLA, P. OLIVIERO, J. L. MARTIN, AND B. SWYNGHEDAUW. Major alterations in relaxation during cardiac hypertrophy induced by aortic stenosis in guinea pig. Circ. Res. 60: 107-116, 1987.

248.   LECLERCQ, J. F., AND B. SWYNGHEDAUW. Myofibrillar ATPase, DNA and hydroxyproline content of human hypertropied heart. Eur. J. Clin. Invest. 6: 27-34, 1976.

249.   LELIÈVRE, L., J. M. MAIXENT, P. LORENTE, C. MOUAS, D. CHARLEMAGNE, AND B. SWYNGHEDAUW. Prolonged responsiveness to ouabain in hypertrophied rat heart: physiological and biological evidence. Am. J. Physiol. 250(Heart Circ. Physiol. 19): H923-H931, 1986.

250.   LE PRIGENT, K., D. LAGADIC-GOSSMANN, AND D. FEUVRAY. Modulation by pH and intracellular Ca²⁺ of Na⁺-H⁺ exchange in diabetic rat isolated ventricular myocytes. Circ. Res. 80: 253-260, 1997.

251.   LEVY, D., K. M. ANDERSON, D. D. SAVAGE, S. A. BALKUS, W. B. KANNEL, AND W. P. CASTELLI. Risk of ventricular arrhythmias in left ventricular hypertrophy: the Framingham heart study. Am. J. Cardiol. 6: 560-565, 1987.

252.   LI, Z., O. H. L. BING, X. LONG, K. G. ROBINSON, AND E. G. LAKATTA. Increased cardiomyocyte apoptosis during the transition from hypertrophy to heart failure in the spontaneously hypertensive rat. Am. J. Physiol. 272(Heart Circ. Physiol. 41): H2313-H2319, 1997.

253.   LIANG, P., AND A. B. PARDEE. Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science 257: 967-971, 1992.

254.   LIMAS, C. J., AND S. S. SPIER. Effect of antihypertensive therapy on calcium transport by cardiac sarcoplasmic reticulum of SHR. Cardiovasc. Res. 14: 692-699, 1980.

255.   LINCK, B., P. BOKNIK, T. ESCHENHAGEN, F. U. MÜLLER, J. NEUMANN, M. NOSE, L. R. JONES, W. SCHMITZ, AND H. SCHOLZ. Messenger RNA expression and immunological quantification of phospholamban and SR-Ca²⁺-ATPase in failing and nonfailing human hearts. Cardiovasc. Res. 31: 625-632, 1996.

256.   LINDPAINTER, K., M. JIN, N. NIEDERMAIER, M. J. WILHEM, AND D. GANTEN. Cardiac angiotensinogen and its local activation in the isolated perfused beating heart. Circ. Res. 67: 564-573, 1990.

257.   LINDPAINTER, K., D. D. LUND, AND P. G. SCHMID. Effects of chronic progressive myocardial hypertrophy on indexes of cardiac autonomic innervation. Circ. Res. 61: 55-62, 1987.

258.   LINZBACH, A. J.. Heart failure from the point of view of quantitative anatomy. Am. J. Cardiol. 5: 370-381, 1960.

259.   LIU, X., Q. SHAO, AND N. S. DHALLA. Myosin light chain phosphorylation in cardiac hypertrophy and failure due to myocardial infarction. J. Mol. Cell. Cardiol. 27: 2613-2621, 1995.

260.   LOMBÉS, M., M. E. OBLIN, J. M. GASC, E. E. BAULIEU, N. FARMAN, AND J. P. BONVALET. Immuno-histochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor. Circ. Res. 71: 503-510, 1992.

261.   LOMMI, J., K. PULKKI, P. KOSKINEN, H. NÄVERI, H. LEINONEN, M. HÄRKONEN, AND M. KUPARI. Haemodynamic, neuroendocrine and metabolic correlates of circulating cytokine concentrations in congestive heart failure. Eur. Heart J. 18: 1620-1625, 1997.

262.   LOMPRÉ, A. M., M. ANGER, AND D. LEVITSKY. Sarco(endo)plasmic reticulum calcium pumps in the cardiovascular system: function and gene expression. J. Mol. Cell. Cardiol. 26: 1109-1121, 1994.

263.   LOMPRÉ, A. M., F. LAMBERT, E. G. LAKATTA, AND K. SCHWARTZ. Expression of sarcoplasmic reticulum Ca²⁺ATPase and calsequestrine genes in rat heart during ontogenic development and aging. Circ. Res. 69: 1380-1388, 1991.

264.   LOMPRÉ, A. M., J. J. MERCADIER, AND K. SCHWARTZ. Changes in gene expression during cardiac growth. Int. Rev. Cytol. 124: 137-187, 1991.

265.   LOMPRÉ, A. M., B. NADAL-GINARD, AND V. MAHDAVI. Expression of the cardiac ventricular  and  myosin heavy-chain genes is developmentally and hormonally regulated. J. Biol. Chem. 255: 6437-6446, 1984.

266.   LOMPRÉ, A. M., K. SCHWARTZ, A. D'ALBIS, G. LACOMBE, N. V. THIEM, AND B. SWYNGHEDAUW. Myosin isozymes redistribution in chronic heart overloading. Nature 282: 105-107, 1979.

267.   LOPEZ, J. J., B. H. LORELL, J. R. INGELFINGER, E. O. WEINBERG, H. SCHUNKERT, D. DIAMANT, AND S. S. TANG. Distribution and function of cardiac angiotensin AT₁- and AT₂-receptor subtypes in hypertrophied rat hearts. Am. J. Physiol. 267(Heart Circ. Physiol. 36): H844-H852, 1994.

268.   LORELL, B. H., L. F. WEXLER, S. I. MOMOMURA, E. WEINBERG, AND C. S. APSTEIN. The influence of pressure overload ventricular hypertrophy on diastolic properties during hypoxia in isovolumically contracting rat hearts. Circ. Res. 58: 653-663, 1986.

269.   LUND, D. D., AND R. J. TOMANEK. The effects of chronic hypoxia on the myocardial cell of normotensive and hypertensive rats. Anat. Rec. 196: 421-430, 1980.

270.   LUO, W., I. L. GRUPP, J. HARRER, S. PONNIAH, G. GRUPP, G. DUFFY, T. DOETSCHMAN, AND E. KRANIAS. Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of -agonist stimulation. Circ. Res. 75: 401-409, 1994.

271.   MACIEL, L. M. Z., R. POLIKAS, D. ROHRER, B. K. POPOVICH, AND W. H. DILLMANN. Age-induced decreases in the messenger RNA coding for the sarcoplasmic reticulum Ca²⁺ ATPase of the rat heart. Circ. Res. 67: 230-234, 1990.