[Hypertension-induced fibrosis: a balance story]. / La fibrose dans l'hypertension artérielle : une histoire d'équilibre.

Cardiac remodeling is a deleterious consequence of arterial hypertension. This remodeling results in cardiac transcriptomic changes induced by mechanical and hormonal factors (angiotensin II and aldosterone are the most important). The major features of cardiac remodeling are the hypertrophy of cardiomyocytes, interstitial and perivascular fibrosis, and microvascular rarefaction. Inappropriate stimulation of the renin-angiotensin-aldosterone system (RAAS) participates to the development of heart failure. The respective roles of angiotensin II and aldosterone in cardiac remodeling are poorly understood. The development of fibrosis in the heart depends of a balance between profibrotic (TGFß, CTGF, inflammation) and antifibrotic (BNP, ANP, BMP4 and BMP7) factors. The profibrotic and proinflammatory effects of angiotensin II and aldosterone are very well demonstrated; however, their actions on antifibrotic factors expression are unknown. In order to explore this, we used RenTgKC mice overexpressing renin into the liver, leading to an increased plasma angiotensin II and thus induction of severe hypertension, and AS mice overexpressing aldosterone synthase (AS) in cardiomyocytes which have a doubled intracardiac aldosterone concentration. Male AS mice have a dysfunction of the coronary arteries relaxation without structural and functional changes of the myocardium. Mice derived from a crossing between the RenTgKC and AS strains were used in this work. It is shown that angiotensin II induces the expression of BNP and BMPs which ultimately slows the progression of myocardial fibrosis, and that aldosterone inhibits the expression of these factors and thus worsens the fibrosis.

Aldosterone and anti-aldosterone effects in cardiovascular diseases and diabetic nephropathy.

Cells in the cortical collecting duct of distal nephron have been considered for a long time as the unique cellular targets of aldosterone. However, it is now clear that other cell types in non-epithelial tissues are also potential targets for aldosterone. The functions that this hormone controls in non-epithelial tissues are still a matter of debate. Clinical and experimental studies have established that aldosterone plays a major role in the pathophysiology of cardiovascular and renal diseases. The aldosterone receptor antagonists spironolactone and eplerenone have demonstrated specific effects not related to their hypotensive properties in hypertension or cardiac diseases. It appears that a key action of these molecules is related to prevention or treatment of end-organ damage. The latter fact, and the recognition of aldosterone escape on long-term treatment of heart failure, diabetic nephropathy and some forms of hypertension with ACE inhibitors, justify the clinical use of aldosterone receptor antagonists provided that kaliemia is controlled. Experimental studies have allowed to draw a still incomplete but comprehensive scheme of aldosterone cardiovascular actions in pathological conditions. When elevated, aldosterone has deleterious effects in blood vessels, in the heart and in kidney, which are secondary to the induction of inflammatory and oxidative processes and necrosis, that induce the increased synthesis of extracellular matrix proteins.

Aldosterone-synthase overexpression in heart: a tool to explore aldosterone's effects.

Clinical observations indicate that elevated aldosterone impairs cardiovascular function. The mechanisms, however, are not totally understood although total and cardiovascular mortality are decreased by aldosterone antagonists. Experimentally, increased plasma aldosterone induces pericoronary inflammation and cardiac fibrosis. Our laboratory has discovered that aldosterone is synthesized in the rat heart, and has demonstrated that this cardiac aldosterone is involved in post-infarction cardiac remodeling. In man, activated cardiac aldosterone production has been described in patients with heart failure. In transgenic mice that overexpress aldosterone-synthase in the heart, we observe a normal cardiac function but a major coronary dysfunction, more pronounced in males. These observations converge to a potential physiological and pathological relevance of this system. Beneficial effects of anti-aldosterone treatment in heart failure may thus be secondary in part to blockade of cardiac aldosterone action.

Different regulation of cardiac and renal corticosteroid receptors in aldosterone-salt treated rats: effect of hypertension and glucocorticoids.

This study analysed the regulation of cardiac mineraloreceptor (MR) and glucoreceptor (GR) in aldosterone-salt treatment (AST). AST causes hypertension, left ventricle (LV) hypertrophy and decreases plasma corticosterone level. Ribonuclease protection assay and Western blot analysis showed a rise of MR mRNA (1.5- and 1.4-fold at day 15 and 30, respectively) and protein levels (1.8- and 4.1-fold at day 30 and 60, respectively) in the LV, but not in either the right ventricle (RV) or in kidney of treated rats. Addition of MR antagonist spironolactone (20 mg/kg/day) for 30 days failed to prevent these changes but was able to reduce AST-induced cardiac fibrosis. Similar hypertension-induced MR upregulations were observed in the LV of AngII-hypertensive rats and of 12-week-old SHR when compared to 4-week-old prehypertensive SHR. AST also enhanced left ventricular GR mRNA (2.0- and 3.0-fold at day 7 and 15, respectively) and protein contents (2.0- and 1.7-fold at day 30 and 60, respectively). In contrast to MR, GR levels were also upregulated in both RV and kidney. Such an upregulation was equally observed at mRNA and protein levels in LV, RV and kidney after adrenalectomy (15 days) and was prevented in both tissues after glucocorticoid replacement (adrenalectomy + dexamethasone at 100 micro g/kg/day for 15 days). Therefore, MR level may be controlled by hemodynamical factors whereas that of GR depends upon glucocorticoids level.

Cardiac aldosterone production and ventricular remodeling.

An intracardiac production of aldosterone has been recently reported in rat. This production is increased both acutely and chronically by angiotensin II, observations suggesting that the heart contains a steroidogenic system that is regulated similarly to the adrenal one. Cardiac production of aldosterone is small compared with that of the adrenal, raising the question of its function in normal conditions. Moreover, the regulation of this synthesis in pathophysiologic states remains unknown. In an analysis of the effects of a one-month myocardial infarction (MI) on the cardiac steroidogenic system, it was observed that aldosterone-synthase mRNA and the aldosterone concentration were increased by 2- and 3.5-fold, respectively, in the noninfarcted part of the rat left ventricle. MI also induced a 1. 9-fold increase in the cardiac angiotensin II level. Losartan prevented these changes, and the MI-induced collagen deposition in noninfarcted area of the left ventricle was reduced by 1.6- and 2. 5-fold by both spironolactone and losartan treatments, respectively. Thus, these observations indicate that MI is associated with tissue-specific activation of myocardial aldosterone synthesis. This activation is mediated by cardiac angiotensin II via the angiotensin II type 1 (AT1) receptor, and the resultant increase of intracardiac aldosterone level may be involved in post-MI ventricular remodeling.

[Role of cardiac aldosterone in post-infarction ventricular remodeling in rats]. / Rôle de l'aldostérone cardiaque dans le remodelage ventriculaire du postinfarctus chez le rat.

Synthesis of aldosterone (Aldo) and corticosterone (B) has been recently reported in rat heart. However, regulation of this synthesis in pathophysiological states remains unknown. Thus, this study aimed to analyze effects of a one-month myocardial infarction (MI) on cardiac steroidogenic system. Levels of terminal enzymes of B (11 beta-hydroxylase: 11 beta H) and aldo (Aldo-synthase: AS) synthesis were assayed by quantitative RT-PCR. Cardiac Aldo and B levels were assessed by celite colum chromatography and radioimmunoassay. MI raised AS mRNA levels by 2.0-fold (p < 0.05) but downregulated that of 11 beta H by 2.4 fold (p < 0.05) in the noninfarcted part of the left ventricle (LV). Cardiac steroids production followed a similar pattern of regulation. Aldo level was increased in MI (319 +/- 85 vs 87 +/- 11 pg/mg of protein in control, p < 0.05) whereas that of B fell (2,412 +/- 318 vs 4,624 +/- 857 pg/mg of protein in control, p < 0.05). MI also induced an 1.9-fold increase in cardiac Ang II level. Such cardiac regulations were prevented by Ang II-AT1 receptor antagonist losartan (8 mg/kg/day) treatment. The Aldo receptor antagonist spironolactone (20 mg/kg/day) had no effect. Plasma Aldo and B, and adrenal 11 beta H and AS mRNA levels were unchanged whatever the treatment. The MI-induced collagen deposition in noninfarcted area of the LV was reduced by both spironolactone and losartan treatments by 1.6- and 2.5-fold, respectively. These data indicate that MI is associated with tissue-specific activation of myocardial aldosterone synthesis. This activation is mediated by cardiac Ang II via AT1 receptor and the resultant increase of intracardiac aldosterone level may be involved in post-MI ventricular remodeling.

Activation of cardiac aldosterone production in rat myocardial infarction: effect of angiotensin II receptor blockade and role in cardiac fibrosis.

BACKGROUND: This study analyzed the regulation and the role of the cardiac steroidogenic system in myocardial infarction (MI). METHODS AND RESULTS: Seven days after MI, rats were randomized to untreated infarcted group or spironolactone- (20 and 80 mg x kg-1 x d-1), losartan- (8 mg x kg-1 x d-1), spironolactone plus losartan-, and L-NAME- (5 mg x kg-1 x d-1) treated infarcted groups for 25 days. Sham-operated rats served as controls. In the noninfarcted myocardium of the left ventricle (LV), MI raised aldosterone synthase mRNA (the terminal enzyme of aldosterone synthesis) by 2. 0-fold and the aldosterone level by 3.7-fold. Conversely, MI decreased 11beta-hydroxylase mRNA (the terminal enzyme of corticosterone synthesis) by 2.4-fold and the corticosterone level by 1.9-fold. MI also induced a 1.9-fold increase in cardiac angiotensin II level. Such cardiac regulations were completely prevented by treatment of the infarcted heart with losartan. The MI-induced collagen deposition in noninfarcted LV myocardium was prevented by 1.6-fold by both low and high doses of spironolactone and by 2.5-fold by losartan. In addition, norepinephrine level was unchanged in infarcted heart but was attenuated by both losartan and spironolactone treatments. CONCLUSIONS: MI is associated with tissue-specific activation of myocardial aldosterone synthesis. This increase is mediated primarily by cardiac angiotensin II via AT1-subtype receptor and may be involved in post-MI ventricular fibrosis and in control of tissue norepinephrine concentration.

Angiotensin AT1 receptor subtype as a cardiac target of aldosterone: role in aldosterone-salt-induced fibrosis.

This study tests the hypothesis that aldosterone induces cardiac fibrosis through an increase of cardiac angiotensin II (Ang II) AT1 receptor levels, thereby potentiating the fibrotic effect of Ang II by determining the effects of spironolactone and losartan on cardiac fibrosis, AT1 density, and gene expression in aldosterone-salt-treated rats. Fibrosis was quantified by slot blots of collagen I and III mRNA levels and videomorphometry of Sirius red-stained collagen. AT1 receptor density was determined by (125I-Sar1-Ile8)-Ang II competition binding, and AT1 mRNA levels were analyzed by quantitative reverse transcriptase polymerase chain reaction. One month of aldosterone-salt treatment induced a decrease in plasma Ang II and an increase in blood pressure, left ventricular hypertrophy, and ventricular fibrosis. Spironolactone (20 mg/kg per day) and losartan spironolactone (10 mg/kg per day) had no effect on the first 3 parameters. Losartan was as effective as spironolactone in preventing ventricular collagen mRNA increase and fibrosis. Ventricular density of AT1 receptors increased 2-fold and was accompanied by a 3-fold increase in the corresponding mRNA in aldosterone-salt compared with sham-operated rats. Both spironolactone and losartan prevented the elevation of ventricular AT1 density and that of right ventricular AT1 mRNA levels. These results demonstrate that the mechanism by which aldosterone-salt induces cardiac fibrosis involves Ang II acting through AT1 receptors. They also suggest that the cardiac AT1 receptor is a target for aldosterone.

In vivo left ventricular function and collagen expression in aldosterone/salt-induced hypertension.

Cardiac fibrosis is linked to aldosterone-induced hypertension, but the effects on in vivo left ventricular (LV) function are not established. We studied the relations between in vivo LV function and aldosterone/salt cardiac fibrosis. Adult guinea pigs (GPs) were treated for 3 months with an aldosterone infusion and high-salt diet. This treatment induced arterial hypertension (+35%) and moderate LV hypertrophy (LVH; +60%) without right ventricular (RV) hypertrophy. Echo-Doppler LV assessment demonstrated unaltered cardiac output, stroke volume, or LV relaxation. Type I collagen messenger RNA (mRNA) was significantly increased in both ventricles (LV, +48%; RV, +77%) and accompanied by a significant increase in total collagen deposition (LV, from 0.52% in controls to 4.4% in treated GPs; RV, from 0.82 to 5.5% in treated GPs). Plasma norepinephrine levels increased 2.6-fold (p < 0.01) and correlated with the increase in collagen deposition in both ventricles. Collagen content was not correlated with hypertension or LVH. We conclude that aldosterone administration induces cardiac collagen accumulation and a sympathetic stimulation, which might preserve systolic and diastolic function.

[The cardiovascular steroid system]. / Le système stéroïde cardiovasculaire.

In this review, the authors describe: (1) the different types of glucocorticoid hormone receptors, on the cell membrane and two types inside the cell, the MR and GR (mineralo- and glucoreceptors); (2) the synthesis of the hormones with the decisive role of the final enzymes, 11 beta-hydroxylase and aldosterone-synthetase; (3) the increasing evidence for a cardiovascular steroid system in the vessels as well as in the myocardium. The authors have reported new data suggesting the existence of an endocrine cardiac steroidogenic system in the heart with a potential physiological and pathological relevance (for transmembrane ion transport and trophic alterations).

Myocardial production of aldosterone and corticosterone in the rat. Physiological regulation.

Increasing evidence suggests that mineralo- and glucocorticoids modulate cardiovascular homeostasis via the effects of circulating components generated within the adrenals but also through local synthesis. The aim of this study was to assess the existence of such a steroidogenic system in heart. Using the quantitative reverse transcriptase-polymerase chain reaction, the terminal enzymes of corticosterone and aldosterone synthesis (11beta-hydroxylase and aldosterone synthase, respectively) were detected in the rat heart. This pathway was shown to be physiologically active, since production of aldosterone, corticosterone, and their precursor, deoxycorticosterone, was detected in both the homogenate and perfusate of isolated rat hearts using radioimmunoassay after Celite column chromatography. Perfusion of angiotensin II or adrenocorticotropin for 3 h increased aldosterone and corticosterone production and decreased deoxycorticosterone, suggesting that aldosterone and corticosterone are formed within the isolated heart from a locally present substrate. Chronic regulation of this intracardiac system was then examined. As in adrenals cardiac 11beta-hydroxylase and aldosterone-synthase mRNAs were independently regulated by 1 week's treatment with either low sodium and high potassium diet (which increased aldosterone synthase mRNA level only), angiotensin II (which raised level of both mRNAs), or adrenocorticotropin (which stimulated the 11beta-hydroxylase gene exclusively). Changes in cardiac steroid levels during treatment were not directly related to their plasma levels suggesting independent regulating mechanisms. This study, therefore, provides the first evidence for the existence of an endocrine cardiac steroidogenic system in rat heart and emphasizes its potential physiological and pathological relevance.

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

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

Differential regulation of matrix metalloproteinases associated with aging and hypertension in the rat heart.

We compared two models of cardiac fibrosis in which collagen synthesis is controlled at different levels. Regulation is pretranslational in aldosterone-salt-induced hypertension in young rats and posttranslational in 24-month-old rats. However, little is known about the role of matrix metalloproteinases (MMP) in fibrosis development. Ventricular MMP activities were studied by zymography, and MMP-2 and MMP-1 mRNA levels were determined using slot-blot and ribonuclease protection assay, respectively. After 1 month of aldosterone-salt treatment, proMMP-2, MMP-2, and proMMP-1 collagenolytic activities and their gene expression were unchanged compared with sham-operated rats. After 2 months, total MMP-2 activity was increased by 40% with parallel stimulation of its gene expression. These changes were localized by in situ zymography within the media of coronary vessels. These results suggest that MMP play a prominent role in vascular remodeling during the first steps of hypertension. During aging, however, there were 40% and 45% decreases in MMP-2 and proMMP-1 activity, respectively, with a corresponding down-regulation of MMP-2 mRNA. These observations suggest that depression of the degradative pathway is partly responsible for age-associated fibrosis. Thus, MMP have differing involvements in the cardiac remodeling associated with hypertension or aging.

Molecular characteristics of cocaine-induced cardiomyopathy in rats.

Cocaine abuse induces severe cardiomyopathy. To investigate the molecular effects of acute and prolonged administration of cocaine, mRNAs encoding markers of either mechanical overload, as atrial natriuretic factor (ANF) and alpha- and beta-myosin heavy chains, or fibrosis as type I and III procollagens, were quantitated in the left ventricle of rats 4 h after one injection of cocaine (40 mg/kg, n = 7), or 14 (n = 15) and 28 days (n = 10) after chronic infusion of cocaine (40 mg/kg per day). Plasma cocaine and benzylecgonine concentrations were both significantly augmented during the infusion while plasma levels of triiodothyronine and thyroxine were lowered. Acute injection of cocaine induced ANF gene expression. Cocaine treatment during 28 days resulted in left ventricular hypertrophy (+ 20% after 24 days, P < 0.05) with normal blood pressure, associated with an accumulation of mRNAs encoding ANF and type I and III collagens (+66% and +55%, P < 0.05). Such a chronic treatment also induced a shift from the alpha- to the beta-myosin heavy chain gene expression (-40% and +50%, P < 0.05). In conclusion, cocaine activates markers of both hemodynamic overload and fibrosis. Such an activation may result from direct and/or indirect effects of the drug such as myocardial ischemia, mechanical overload and/or hypothyroidism.

Biological determinants of aldosterone-induced cardiac fibrosis in rats.

To determine the events leading to cardiac fibrosis in aldosterone-salt hypertensive rats, we studied protein and mRNA accumulation of procollagens I and III for 60 days. After 3 and 7 days of treatment systolic pressure was normal, and no histological or biochemical changes were seen in rat hearts. At day 15 arterial pressure was raised (+40%) and left ventricular hypertrophy was +15%. Cardiac examination after hemalun-eosin staining and immunolabeling with anticollagen I and III antibodies showed no structural alterations, but an 83% increase in right ventricular type III procollagen mRNA levels was found. At 30 and 60 days we found progressive cardiac fibrosis, with inflammatory cells, myocyte necrosis, and elevation of both types I and III procollagen mRNA levels in both ventricles. To determine whether aldosterone had effects on Na,K-ATPase that might lead to ionic disturbances and induce myocyte necrosis, we studied the major cardiac Na,K-ATPase isoform genes. Although Na,K-ATPase alpha 1- and beta 1-subunit mRNA levels were elevated in kidney at day 1, neither of these cardiac transcripts nor the specific alpha 2 isoform was altered between 1 and 15 days. These results show that accumulation of procollagen mRNAs occurs before collagen deposition. Cardiac alterations are late and not preceded by changes in Na,K-ATPase cardiac gene expression, precluding a direct modulation of cardiac collagen synthesis and Na,K-ATPase by aldosterone.

Molecular and cellular biology of the senescent hypertrophied and failing heart.

During aging, experimental studies have revealed various cellular changes, principal among which is myocyte hypertrophy, which compensates for the loss of myocytes and is associated with fibrosis. The expression of alpha-myosin heavy chain is replaced by that of the isogene beta-myosin, which leads to decreased myosin adenosine triphosphatase (ATPase) activity. In consequence, contraction is slower and more energetically economical. The Ca(2+)-ATPase of the sarcoplasmic reticulum and Na+/Ca2+ exchange activity are decreased, which probably explains the reduced velocity of relaxation. Membrane receptors are also modified, since the density of both the total beta-adrenergic and muscarinic receptors is decreased. The senescent heart is able to hypertrophy in response to overload and to adapt to the new requirements. Similar alterations are observed both in the senescent heart and in the overloaded heart, in clinical as well as in experimental studies; however, differences do exist, especially in terms of fibrosis and arrhythmias.

Angiotensin converting enzyme inhibition prevents proto-oncogene expression in the vascular wall after injury.

OBJECTIVES: Angiotensin converting enzyme (ACE) inhibitors reduce neointimal hyperplasia after balloon denudation, but the mechanisms are not completely understood. It has been demonstrated that nuclear oncogenes are induced in the vascular wall in the hours immediately after injury, and that the same genes are induced by angiotensin II in vascular smooth muscle cells. It has therefore been suggested that the effects of ACE inhibitors on the response of the vessel wall could be mediated by an inhibition of proto-oncogene expression. METHODS AND RESULTS: Sixteen New Zealand White rabbits were randomly assigned for histologic analysis to receive placebo (n = 9) or 1 mg/kg per day perindopril (n = 7). After treatment for 7 days balloon aortic injury was performed. The treatment was continued and the rabbits were killed 28 days after injury. In the perindopril group the neointimal cross-sectional area was significantly smaller than in the control group. Six untreated rabbits were used to assess the time course of proto-oncogene expression in the aortic wall after injury in the present model. After extraction, total aortic RNA was hybridized with myc, fos and jun probes. Based on the results, the effects of ACE inhibition on proto-oncogene expression were tested 1 h after balloon denudation. Accordingly, 24 rabbits were randomly assigned to pretreatment for 7 days with placebo or with 1 or 10 mg/kg per day perindopril (n = 8, for each group) and were killed 1 h after injury. Expression of c-myc was not altered by pretreatment. However, 1 mg/kg per day perindopril induced significant reductions of 50% in c-jun and 45% in c-fos expression compared with control. No additional effect was obtained with the higher dose. CONCLUSION: The effect of ACE inhibition on intimal hyperplasia is associated with a reduction in early cellular events such as c-fos and c-jun expression. These results suggest that potent ACE inhibition at the time of vascular injury may be required to limit the hyperplastic response of the vessel wall.

Nonsynchronous changes in myocardial collagen mRNA and protein during aging: effect of DOCA-salt hypertension.

Myocardial fibrosis has been investigated in 3-, 16-, and 24-mo-old normal rats and also in 24-mo-old rats subjected to deoxycorticosterone acetate (DOCA)-salt treatment-induced-hypertension. Collagen content was assessed both histologically and by hydroxyproline assay. Type I and III procollagen mRNA levels were quantitated by Slot Blot analyses. Aging is associated with fibrosis as shown both biochemically (hydroxyproline concentration in 3-, 16-, and 24-mo-old rats was 0.70 +/- 0.05, 0.92 +/- 0.07, and 1.57 +/- 0.13 mg/g of left ventricle, respectively, P < 0.05 and P < 0.0001 vs. 3 mo) and histologically. By contrast, type I procollagen mRNA levels decreased during aging (from -63%, P < 0.001 in 16-mo-old rats and -51%, P < 0.01 in 24-mo-old rats vs. 3-mo-old rats) as well as type III procollagen mRNA levels. DOCA-salt treatment in 24-mo-old rats had no effect on either the degree of fibrosis or the mRNA levels. We conclude that nonsynchronous changes in myocardial collagen mRNA and protein occur during aging, indicating translational and/or posttranslational mechanisms in collagen regulation. Hypertension during senescence did not modify collagen deposition at either the protein or mRNA levels.

Is the senescent heart overloaded and already failing?

Heart failure mainly occurs during the last decades of life, and it is important to know if the senescent heart is not an already failing heart. During aging, both contraction and relaxation of papillary muscle are impaired. Such an impairment is compensated in vivo and the cardiac output remains normal. In spite of a loss in myocytes, the heart weight/body weight ratio is unchanged, but the myocytes are bigger. Arrhythmias are permanent and are accompanied by a loss of the normal heart rate variability. Changes in specific mRNAs include: a shift in myosin heavy chain (MHC) isogene expression leading to an increased beta MHC content; decreased densities of Ca2+ ATPase of the sarcoplasmic reticulum, beta 1-adrenergic receptor, and muscarinic receptors; and attenuation of the Na+/Ca2+ exchange activity. Most of these changes, but not all, resemble those observed during cardiac overload and are accompanied by an increased duration of both the action potential and the intracellular calcium transient. However, the senescent heart is still able to further modify its phenotype in response to mechanical overload. The senescent heart is a diseased heart, and the origin of the "disease" is multifactorial and includes the general process of senescence, hormonal changes, and the myocardial consequences of senescence of the vessels.