Postinfarction myocardial remodeling: current treatment

Ronnie Willenheimer
Department of Cardiology, University Hospital Malmö, Lund University, Malmö, Sweden
Correspondence: Dr Ronnie Willenheimer, Department of Cardiology, University Hospital Malmö, 205 02 Malmö, Sweden. Tel: +46 40 331000, fax: +46 40 336209,
e-mail: ronnie.willenheimer@medforsk.mas.lu.se

Introduction
The myocardial remodeling process can be adaptive in response to intermittent physiological stimuli such as exercise training. However, after a myocardial infarction the stimuli are continuous and pathological. Therefore, the process becomes maladaptive, leading to progressive myocardial dysfunction.[1] Even if the infarction is so small that it causes no immediate cardiac dysfunction the remodeling process is triggered. The progressive changes in myocardial structure and deterioration of myocardial function can go on silently for a long time. Consequently, in the absence of further clinical ischemic events, overt heart failure may not develop until several years after an infarction. Since the remodeling process is
triggered in virtually all patients with a myocardial infarction, it is imperative to counteract this process immediately following the infarct in order to decrease morbidity and prolong life.

What is remodeling?
In clinical practice ‘remodeling’ usually denotes left ventricular dilatation and altered geometry with a more spherical left ventricle, which is seen in a number of cardiac disorders.[1] This is usually accompanied by a decreased ejection fraction. However, at the microscopic level a number of changes are found (Table I).

Table I. Features of remodeling.



The basis for myocardial remodeling is the phenotype alteration, caused by reexpression of fetal genes in response to pathological stimuli (Figure 1).[2,3]

Figure 1. In response to pathological stimuli, genes coding for fetal proteins, which normally are not expressed in the adult human, once again become available for transcription.

This leads to rapid myocardial growth, attempting to compensate for the increased mechanical load imposed on the myocardium following a myocardial infarction.[4] The increased myocardial mass is partly due to myocyte hypertrophy. However, the quality of these proteins is not appropriate to meet the demands on the myocardium of the adult human, which eventually leads to myocardial dysfunction.
Another result of the altered gene expression is collagen deposition, causing diffuse interstitial fibrosis, perivascular fibrosis, and focal, reparative fibrosis.[1,5] As a result the myocardium becomes less compliant and diastolic dysfunction develops. Perivascular fibrosis impairs the coronary artery compliance and decreases the coronary reserve, which increases myocardial ischemia (Figure 2).[6]

Figure 2. Perivascular fibrosis impairs coronary vessel compliance and decreases the ability of the coronary arteries to increase the blood flow in response to increased demand, ie, the coronary reserve (reproduced from reference 1).

Furthermore, fibrosis may promote ventricular arrhythmia.[5,7] The fibrous tissue is vital and contains viable cells. Thus, there is a continuous deposition of collagen by fibroblasts and consumption by macrophages. These cells consume oxygen, energy, and nutrients, causing a corresponding deficiency in the working myocytes. This leads to continuous myocyte death and systolic ventricular dysfunction.
In the remodeled myocardium there is a vascular deficit (Figure 3) which further contributes to impaired supply of oxygen and nutrients to vital myocardial cells[1] and promotes progressive cell death and remodeling. Myocyte hypertrophy also causes a relative decrease in the density of mitochondria, leading to insufficient energy production and myocardial dysfunction.[1]


Figure 3. The remodeled myocardium is characterized by reduced vessel density (reproduced from reference 1)

The remodeled myocardium is also characterized by deficient Ca2+ handling due to a relative decrease of sarcoplasmic reticulum, Ca2+ channels, and Ca2+ pumps.[1,3,8] Due to the altered gene expression there is also an impaired quality of Ca2+ handling proteins.[9] This contributes to the myocardial dysfunction.
Another feature of myocardial remodeling is a shift towards slower isoforms of myosin,[10] causing slowing of myocardial contractility and contributing to the myocardial dysfunction.
An important characteristic of myocardial remodeling is myocyte death, which can be either necrotic or apoptotic.[11] Death of myocytes leads to fibrosis and thus increased remodeling, since the lost cells are replaced by collagen in order to avoid empty spaces in the myocardium (Figure 4).[11]

Figure 4. Death of myocytes leads to increased remodeling. The load on the remaining myocytes is increased, which further promotes the remodeling process. Furthermore, lost myocytes are replaced by collagen (reparative fibrosis) in order to avoid empty spaces in the myocardium. This constitutes an increase of the remodeling per se (reproduced from reference 1).






Main stimuli for remodeling
The main stimuli for myocardial remodeling are mechanical overload and activation of neurohormonal systems such as the angiotensin and sympathico-adrenergic systems.[12] The mechanical overload triggers neurohormonal activation[13] and other cellular mediators of remodeling (Table II).

Table II. Remodeling mediators and targets for antiremodeling therapy.

Together they cause the remodeling events (Figure 5). Consequently, the mechanical overload and the remodeling mediators are the targets for therapy aimed at slowing or possibly stopping the remodeling process.



Figure 5. The main stimuli for myocardial remodeling are mechanical overload and activation of neurohormonal systems. The mechanical overload triggers neurohormonal activation and other cellular mediators of remodeling. Together they cause the remodeling events leading to disease.





Antiremodeling therapy
b-Receptor blockers
Norepinephrine can induce remodeling events such as reinduction of fetal genes, growth of cardiac myocytes, increased synthesis of DNA and protein in cardiac fibroblasts, downregulation of calcium-regulating genes, expression of tumor growth factors, and apoptosis.[1,2] b-Receptor blocking agents may inhibit remodeling by counteracting these effects of norepinephrine. Mortality and morbidity were substantially reduced in postinfarct patients with asymptomatic left ventricular systolic dysfunction treated by carvedilol (the CAPRICORN trial, presented by H. Dargie at the 2001 ACC meeting in Orlando,), and in patients with chronic heart failure treated by carvedilol[14] (the COPERNICUS trial, presented by M. Packer at the 2001 ACC meeting in Orlando), bisoprolol,[15] and metoprolol.[16] The mortality reduction has been shown to be associated with a beneficial effect on myocardial remodeling.[17]

ACE inhibitors and angiotensin receptor blockers
Besides the circulating, endocrine renin-angiotensin-aldosterone system, there is a local paracrine/autocrine angiotensin system in the myocardium.[18] After a myocardial infarction this system is further activated and there is an upregulation of ACE,[19] angiotensinogen mRNA,[20] and angiotensin receptors.[21] Angiotensin II causes remodeling through several mechanisms, including protein synthesis in cardiac myocytes, DNA synthesis in cardiac fibroblasts, and apoptosis.[1] ACE inhibitors and angiotensin receptor blockers (ARBs) may inhibit these events by counteracting the formation of angiotensin II and by blocking the effects of angiotensin II on the angiotensin type-1 receptor, respectively. Indeed, both the ACE inhibitor captopril and the ARB losartan have been found to prevent changes in gene expression and subsequent subcellular remodeling in the remodeled rat heart.[22]
Clinically, ACE inhibition attenuates remodeling following myocardial infarction.[23] Furthermore, ACE inhibition reduces mortality and morbidity in chronic heart failure,[24] in cardiac failure after myocardial infarction,[25] as well as in asymptomatic left ventricular systolic dysfunction.[25,26] However, there are some suggestions of formation and deleterious effects of angiotensin II despite ACE inhibition.[27] Therefore, ARBs alone or in combination with ACE inhibitors may prove more efficacious.[27] However, in the Val-HeFT trial (presented by J. Cohn at the 2000 AHA meeting in New Orleans), treatment with an ARB on top of an ACE inhibitor failed to reduce one of the primary objectives (all cause mortality) in heart failure patients compared with ACE inhibition alone. This combined treatment reduces the second primary objective of mortality and hospitalization. Several clinical studies in cardiovascular disease have shown that angiotensin receptor blockers are at least equal to ACE inhibitors in terms of clinical effects.[27] However, to date there is no evidence that angiotensin receptor blockers are better than, or even similarly efficacious to, ACE inhibitors with regard to mortality and morbidity.[28]

Aldosterone receptor blockers
Aldosterone is especially important to the development of myocardial fibrosis.[29] By inhibiting the formation of aldosterone and/or by blocking the effects of aldosterone at the receptor level myocardial fibrosis may be counteracted. Some of the beneficial effects of ACE inhibition are most likely due to inhibition of aldosterone effects. However, despite treatment with target doses of ACE inhibitors there is considerable formation of aldosterone,30 and the addition of an aldosterone receptor blocker, spironolactone, on top of an ACE inhibitor further reduced mortality in patients with chronic heart failure.[30]

Endothelin-1 receptor blockers
Endothelin-1 is a potent peptide vasoconstrictor produced by several cell types in the myocardium. Endothelin-1 and endothelin receptors are upregulated in the remodeled myocardium.[31] In the rat, endothelin-1 increases collagen synthesis in cardiac fibroblasts,[32] and ventricular myocyte protein synthesis.[33] Blockade of the endothelin-A receptor may counteract remodeling,[34] and has been shown to increase survival in rats after myocardial infarction.[34] Preliminary clinical data suggest beneficial effects of endothelin-inhibiting agents in patients with heart failure.[35,36] However, so far no benefit has been demonstrated on morbidity and mortality. The Randomized Intravenous TeZosentan 1 (RITZ-1) trial (www.theheart.org, April 20, 2001) was recently reported to show no such benefit of the dual endothelin receptor blocker tezosentan in acute heart failure.

Antioxidants
Free oxygen radicals are associated with cardiac myocyte apoptosis, fetal gene expression, and excessive myocardial growth due to increased protein synthesis and fibroblast proliferation.[1,2] There is thus a potential role for antioxidant therapy in conditions with cardiac remodeling. Some of the beneficial effects of carvedilol in patients with heart failure may be due to such an effect.37 Nitric oxide-releasing agents may counteract apoptosis by attenuating free oxygen radicals.[1]

Cytokine antagonists
Inflammatory cytokines such as tumor necrosis factor-a (TNFa) and interleukin-6 are increased in heart failure,[38] and TNFa correlates with survival in patients with heart failure.[38] Cytokines are associated with remodeling and may act via receptors on myocytes and fibroblasts.[39] TNFa antagonism has been well tolerated and seemingly effective in small clinical studies in heart failure patients.[40,41] Nevertheless, two morbidity/mortality trials investigating the TNFa blocker etanercept were recently prematurely halted because of a lack of efficacy (www.theheart.org, March 23, 2001).

Peptide growth factor inhibitors
Peptide growth factors such as fibroblast growth factors, transforming growth factor-b1, and platelet-derived growth factor, are involved in the remodeling process by inducing fetal gene expression and stimulating growth of cardiac myocytes and fibroblasts.[42] Today they may be indirectly inhibited by therapies reducing mechanical overload and by agents blocking the neurohormonal activation responsible for their activation, such as b-receptor blockers.[2]

Therapeutic strategies
Despite ACE inhibitor treatment, mortality remains extremely high in heart failure.[24,25] Although the addition of a b-receptor blocker[14–16] or spironolactone[30] on top of an ACE inhibitor has improved survival somewhat further, it may be necessary to further block the remodeling-mediating pathways in order to completely prevent or stop the remodeling process. However, it has been suggested that it might be dangerous to block the neurohormonal systems too vigorously, and polypharmacy has potential drawbacks.[43] Therefore, individual tailoring of heart failure therapy is probably a useful approach, about which we need to learn more.[43]
When heart failure has developed, the remodeling process is already advanced. It will probably be extremely difficult to fundamentally affect prognosis if therapy is not initiated until the late stages of remodeling. Therefore, it is imperative that we find and appropriately treat patients at risk of developing remodeling, or with remodeling in earlier stages (Figure 6).

Figure 6. The impact of earlier initiated antiremodeling therapy on disease progression, symptom development, and survival.
The y-axis depicts the progression of the disease and remodeling processes. The x-axis represents time. The light grey field indicates that the patient is asymptomatic, and the darker grey field that the patient is symptomatic. Dotted green line: Natural course of the disease (eg, post myocardial infarction). The disease progresses silently with time. After some time the patient becomes symptomatic. At this stage the disease and remodeling processes progress even faster, and the patient eventually dies. Solid green line: If antiremodeling therapy is not initiated until symptoms of heart failure have developed (green asterisk), the disease and remodeling processes are advanced. Although the speed of progression can be slowed, this therapeutic strategy has a small effect on survival and the patients usually continue to be symptomatic. Pink line: When antiremodeling therapy is initiated in early stages of the disease (pink asterisk) the remodeling process is less advanced. Therapy will slow down the remodeling process and disease progression. This therapeutic strategy has a greater impact on survival and the patient may stay asymptomatic for long time. Blue line: The start of antiremodeling therapy in very early stages of the disease or even in patients at risk of developing remodeling has a great impact on survival. The patient may remain asymptomatic for a long time.

Indeed, the HOPE trial44 showed that in patients who mainly had coronary artery disease, early ACE inhibitor therapy has substantial beneficial effects on disease progression and mortality, despite the absence of heart failure and clear left ventricular systolic dysfunction.

REFERENCES 

 
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Left ventricular remodelling and dysfunction. Can the process be prevented?

Willenheimer R.

Lund University, Department of Cardiology, University Hospital Malmo, Malmo, Sweden. ronnie.willenheimer@medforsk.mas.lu.se

Due to continuous remodelling myocardial dysfunction is a progressive condition. Even if the initial event is so mild that it causes no immediate cardiac dysfunction (e.g. a small myocardial infarction), the remodelling process is triggered. Although the remodelling process can be adaptive, the process becomes maladaptive when the stimuli are continuous and pathological. A similar remodelling process is seen in most primary myocardial disorders, suggesting common mechanisms for the development of heart failure. Although clinical heart failure may develop acutely, for example, after an acute myocardial infarction, the progressive changes in myocardial structure and deterioration of myocardial function can go on silently for a very long time and overt heart failure may develop several years after an initial insult, even if there are no further events. In order to fundamentally improve prognosis in cardiac failure it is necessary to identify patients with an ongoing remodelling process and to effectively counteract this process as early as possible.

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2: Am J Cardiol 1997 Dec 4;80(11A):15L-25L Related Articles, Books, LinkOut

Molecular and cellular mechanisms of myocardial failure.

Colucci WS.

Myocardial Biology Unit, Boston University School of Medicine, Massachusetts, USA.

Myocardial remodeling is a central feature in the progression of myocardial failure. This process, which can be stimulated by factors that are increased as a result of myocardial dysfunction such as mechanical stress, angiotensin, and norepinephrine, consists of a variety of molecular and cellular events that can lead to important changes in myocardial structure and function (or phenotype). These alterations include hypertrophy and cellular apoptosis of myocytes, changes in the molecular phenotype of the myocardium with reinduction of a fetal gene program, and alterations in the quantity and composition of the extracellular matrix. Agents that counteract these factors, such as vasodilators, angiotensin-converting enzyme inhibitors, and beta-adrenergic antagonists, slow the progression of myocardial failure and are of clinical value in the treatment of heart failure. Several additional mechanisms have recently been identified that could also be important in mediating myocardial remodeling. These include oxidative stress, inflammatory cytokines, nitric oxide, endothelin, and peptide growth factors. It is likely that additional strategies to inhibit these mechanisms will exert beneficial effects on the process of myocardial remodeling and the development of clinical heart failure.

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3: Physiol Rev 1999 Jan;79(1):215-62 Related Articles, Books, LinkOut
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Molecular mechanisms of myocardial remodeling.

Swynghedauw B.

Institut National de la Sante et de la Recherche Medicale U. 127, Hopital Lariboisiere, Paris, France.

"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 factor and the renin-angiotensin system, and a diminished concentration of sarcoplasmic reticulum Ca2+-ATPase, beta-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.

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  • Review, Academic


PMID: 9922372 [PubMed - indexed for MEDLINE]

 
4: Circulation 1997 Dec 2;96(11):4065-82 Related Articles, Books, LinkOut
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Extracellular matrix remodeling in heart failure: a role for de novo angiotensin II generation.

Weber KT.

Department of Internal Medicine, University of Missouri Health Sciences Center, Columbia 65212, USA.

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PMID: 9403633 [PubMed - indexed for MEDLINE]

 
5: Basic Res Cardiol 1992;87 Suppl 1:291-301 Related Articles, Books, LinkOut

Factors associated with reactive and reparative fibrosis of the myocardium.

Weber KT, Brilla CG.

Division of Cardiology, University of Missouri-Columbia.

Myocardial fibrosis can be defined as an abnormal increase in collagen concentration of either ventricle. This accumulation of collagen, represented predominantly by fibrillar type I collagen, can occur a) on a reactive basis in the interstitial space and adventitia of intramyocardial coronary arteries and does not require myocyte necrosis, or b) as a replacement for necrotic myocytes, where it is considered a scar. Both forms can be found in the same ventricle. Various factors have been found to contribute to the reactive and reparative fibrosis that appears in both ventricles in acquired hypertension. In the case of microscopic scarring, myocyte necrosis is related to catecholamine or angiotensin II- mediated toxicity, reduced potassium stores that accompany chronic mineralocorticoid excess, and coronary vascular remodeling. Reactive fibrosis is associated with elevations in plasma aldosterone concentrations that are inappropriate relative to dietary sodium intake. These findings set the stage for additional in vivo and in vitro studies that may shed more light on our understanding of the factors that regulate the accumulation of fibrous tissue in the myocardium--a major determinant of pathologic structural remodeling which enhances its susceptibility to reentrant arrhythmias and ventricular dysfunction.

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  • Review
  • Review, Tutorial


PMID: 1497573 [PubMed - indexed for MEDLINE]

 
6: Hypertension 1996 May;27(5):1031-8 Related Articles, Books, LinkOut
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Improvement of coronary flow reserve after long-term therapy with enalapril.

Motz W, Strauer BE.

Department of Medicine, Ernst-Moritz-Arndt-University of Greifswald, FRG.

To date, no clinical study shows an improvement in coronary flow reserve due to long-term antihypertensive therapy. in view of the contribution of the renin-angiotensin system to the process of hypertensive remodeling of the heart and coronary circulation, angiotensin-converting enzyme (ACE) inhibitors might act as cardioreparative drugs in arterial hypertension. Accordingly, our objective in this investigation was to examine under clinical conditions to what extent long-term antihypertensive treatment with an angiotensin-converting enzyme inhibitor improved the diminished coronary flow reserve in hypertensive patients with microvascular angina pectoris. For the purpose of comparison, we also treated a normotensive control group of 6 patients with hypertrophic nonobstructive cardiomyopathy. Fifteen hypertensive individuals (10 men, 5 women; age, 58 +/- 6 years) were treated with enalapril (10 to 20 mg/d; mean, 16.7 +/- 4.9 mg/d) for 11 to 13 months. At the end of the treatment period, systolic pressure decreased from 178 +/- 14 to 137 +/- 12 mm Hg and diastolic pressure from 102 +/- 11 to 86 +/- 4 mm Hg under ambulatory conditions. Left ventricular muscle mass index decreased by 8%, from 149 +/- 32 to 137 +/- 28 g/m2 (P < .05). Maximal coronary blood flow after dipyridamole was increased by 43%, from 181 +/- 69 to 258 +/- 116 mL/min per 100 g (P < .001), and minimal coronary vascular resistance was diminished by 29%, from 0.66 +/- 0.23 to 0.47 +/- 0.24 mm Hg x min x 100g x mL-1 (P < .001) after enalapril treatment. Consequently, the calculated coronary reserve increased from 2.2 +/- 0.6 to 3.3 +/- 1.2 (P < .001). After enalapril therapy, the functional class of angina pectoris according to the Canadian classification system had changed from 2.5 +/- 0.6 to 1.5 +/- 0.6 (P < .01). The maximal working capacity had increased from 23.775 +/- 3.970 to 26.255 +/- 4.598 J (mean +/- SE, P < .05). The maximal ST-segment depression at maximal work-load was reduced from 0.18 +/- 0.02 to 0.06 +/- 0.02 (mean +/- SE, (P < .01). In summary, long-term therapy with the angiotensin-converting enzyme inhibitor enalapril must be considered a cardioreparative treatment with respect to the coronary microcirculation in hypertensive heart disease.

Publication Types:
  • Clinical Trial


PMID: 8621193 [PubMed - indexed for MEDLINE]

 
7: Am J Cardiol 1993 Jan 21;71(3):46A-54A Related Articles, Books, LinkOut

Role of mechanical and hormonal factors in cardiac remodeling and the biologic limits of myocardial adaptation.

Klug D, Robert V, Swynghedauw B.

Service de Cardiologie A, Hopital Cardiologique, Lille, France.

Patients with chronic congestive heart failure manifest > or = 1 of the following abnormalities: diastolic dysfunction, systolic dysfunction, and arrhythmias. Diastolic dysfunction, one of the first symptoms to occur during hypertensive cardiopathy, depends on both active relaxation of the cardiac muscle and passive ventricular compliance. The ability of the ventricles to relax depends on normal calcium metabolism and adenosine triphosphate concentration. Ability to extrude intracellular calcium is depressed in the hypertrophied, overloaded heart as compared with the normal myocardium. Myocardial fibrosis is the major cause of increased diastolic ventricular stiffness. Left ventricular (LV) hypertrophy and myocardial fibrosis also greatly increase the likelihood of ventricular arrhythmias, in particular by prolonging the QRS interval and facilitating the occurrence of reentry arrhythmias. Findings in animal studies have indicated that such fibrosis, which involves excessive collagen deposition, is independent of LV hypertrophy and that LV hypertrophy does not necessarily result in myocardial fibrosis. Instead, the development of myocardial fibrosis is sensitive to circulating levels of both angiotensin II and aldosterone, and the fibrotic response to each of these substances is independent. The aldosterone antagonist spironolactone prevents myocardial fibrosis in several animal models, thus confirming the importance of aldosterone in the genesis of excessive collagen deposition.

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  • Review
  • Review, Tutorial


PMID: 8422005 [PubMed - indexed for MEDLINE]

 
8: Circ Res 1993 Feb;72(2):463-9 Related Articles, Books, LinkOut

Alterations in sarcoplasmic reticulum gene expression in human heart failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium.

Arai M, Alpert NR, MacLennan DH, Barton P, Periasamy M.

Department of Physiology and Biophysics, University of Vermont College of Medicine, Burlington.

Recent studies have shown that intracellular Ca2+ handling is abnormal in the myocardium of patients with end-stage heart failure. Muscles from the failing hearts showed a prolonged Ca2+ transient and a diminished capacity to restore a low resting Ca2+ level during diastole. Accordingly, we examined whether this defect in Ca2+ transport function is due to alterations in sarcoplasmic reticulum gene expression. We determined the messenger RNA (mRNA) levels of sarcoplasmic reticulum Ca2+ transport proteins in failing human hearts from 17 cardiac transplant recipients with a diagnosis of dilated cardiomyopathy, primary pulmonary hypertension, or ischemic heart disease. The expression levels of each mRNA were compared with each other and then correlated with that of atrial natriuretic factor (ANF) mRNA in the failing ventricle. The mRNA levels for the calcium release channel (ryanodine receptor, RYR2), Ca2+ uptake pump (Ca(2+)-ATPase, SERCA2 isoform), and phospholamban differed significantly between heart samples but showed an inverse relation with that of ventricular ANF mRNA. In contrast, calsequestrin mRNA levels remained unchanged in these failing hearts. In addition, beta-myosin and alpha-cardiac actin mRNA levels also showed an inverse relation with ANF mRNA levels. These changes were observed in both right and left ventricles of hearts with congestive heart failure due to dilated cardiomyopathy, primary pulmonary hypertension, or ischemic heart disease. The results are consistent with the hypothesis that abnormal calcium handling in the sarcoplasmic reticulum of failing hearts is due to the altered expression of the genes encoding sarcoplasmic reticulum proteins.

PMID: 8418995 [PubMed - indexed for MEDLINE]
 
9: Science 1997 May 2;276(5313):800-6 Related Articles, Books, LinkOut

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Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure.

Gomez AM, Valdivia HH, Cheng H, Lederer MR, Santana LF, Cannell MB, McCune SA, Altschuld RA, Lederer WJ.

Department of Physiology and the Medical Biotechnology Center, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA. Universit.

Cardiac hypertrophy and heart failure caused by high blood pressure were studied in single myocytes taken from hypertensive rats (Dahl SS/Jr) and SH-HF rats in heart failure. Confocal microscopy and patch-clamp methods were used to examine excitation-contraction (EC) coupling, and the relation between the plasma membrane calcium current (ICa) and evoked calcium release from the sarcoplasmic reticulum (SR), which was visualized as "calcium sparks." The ability of ICa to trigger calcium release from the SR in both hypertrophied and failing hearts was reduced. Because ICa density and SR calcium-release channels were normal, the defect appears to reside in a change in the relation between SR calcium-release channels and sarcolemmal calcium channels. beta-Adrenergic stimulation largely overcame the defect in hypertrophic but not failing heart cells. Thus, the same defect in EC coupling that develops during hypertrophy may contribute to heart failure when compensatory mechanisms fail.

PMID: 9115206 [PubMed - indexed for MEDLINE]

 
10: J Clin Invest 1997 Nov 1;100(9):2315-24 Related Articles, Books, LinkOut
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Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.

Lowes BD, Minobe W, Abraham WT, Rizeq MN, Bohlmeyer TJ, Quaife RA, Roden RL, Dutcher DL, Robertson AD, Voelkel NF, Badesch DB, Groves BM, Gilbert EM, Bristow MR.

Division of Cardiology, University of Colorado Health Sciences Center, Denver 80262, USA.

Using quantitative RT-PCR in RNA from right ventricular (RV) endomyocardial biopsies from intact nonfailing hearts, and subjects with moderate RV failure from primary pulmonary hypertension (PPH) or idiopathic dilated cardiomyopathy (IDC), we measured expression of genes involved in regulation of contractility or hypertrophy. Gene expression was also assessed in LV (left ventricular) and RV free wall and RV endomyocardium of hearts from end-stage IDC subjects undergoing heart transplantation or from nonfailing donors. In intact failing hearts, downregulation of beta1-receptor mRNA and protein, upregulation of atrial natriuretic peptide mRNA expression, and increased myocyte diameter indicated similar degrees of failure and hypertrophy in the IDC and PPH phenotypes. The only molecular phenotypic difference between PPH and IDC RVs was upregulation of beta2-receptor gene expression in PPH but not IDC. The major new findings were that (a) both nonfailing intact and explanted human ventricular myocardium expressed substantial amounts of alpha-myosin heavy chain mRNA (alpha-MHC, 23-34% of total), and (b) in heart failure alpha-MHC was downregulated (by 67-84%) and beta-MHC gene expression was upregulated. We conclude that at the mRNA level nonfailing human heart expresses substantial alpha-MHC. In myocardial failure this alteration in gene expression of MHC isoforms, if translated into protein expression, would decrease myosin ATPase enzyme velocity and slow speed of contraction.

PMID: 9410910 [PubMed - indexed for MEDLINE]
 
11: Curr Opin Cardiol 1998 Sep;13(5):317-25 Related Articles, Books, LinkOut

Apoptosis in hypertensive heart disease.

Diez J, Fortuno MA, Ravassa S.

Vascular Pathophysiology Unit, School of Medicine, University of Navarra, Pamplona, Spain.

Numerous hypotheses have been considered to explain the fundamental mechanism(s) for the development of systolic dysfunction and heart failure in animals and humans with arterial hypertension. Besides contractile disturbances of cardiomyocytes and interstitial and perivascular fibrosis, cardiomyocyte loss is now being considered as one of the determinants of the maladaptive processes implicated in the transition from compensated to decompensated left ventricular hypertrophy. A number of experimental evidence suggest that exaggerated apoptosis may account for the loss of cardiomyocytes in the hypertensive left ventricle. Furthermore, some factors intrinsic and extrinsic to the cardiomyocyte emerge as potential candidates to trigger apoptosis. The elucidation of the possible interactions between these factors may be of major interest to prevent the progression to heart failure in patients with hypertensive heart disease.

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  • Review
  • Review, Tutorial


PMID: 9823788 [PubMed - indexed for MEDLINE]

 
12: Cardiovasc Res 1998 Aug;39(2):267-75 Related Articles, Books, LinkOut
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Cellular and molecular aspects of contractile dysfunction in heart failure.

Mittmann C, Eschenhagen T, Scholz H.

Abteilung Allgemeine Pharmakologie, Universitats-Krankenhaus Eppendorf, Hamburg, Germany. mittmann@plexus.uke.uni-hamburg.de

A number of molecular and cellular alterations have been identified in the failing human heart that help to understand contraction and relaxation abnormalities. Cyclic AMP dependent pathways are desensitized due to quantitative changes in beta-adrenoceptors, beta-adrenoceptor kinase, and inhibitory G-proteins. Calcium homeostasis is impaired, characterized by a decreased calcium reuptake rate of the sarcoplasmic reticulum, an increased threshold of the calcium release channel, and an increased Na+/Ca2+ exchanger expression. Myofibrillar function may be affected by a decrease in Mg2(+)-ATPase activity and in troponin I phosphorylation, and by changes in TnT isoform expression. These alterations seem to occur independently of the underlying etiology of heart failure and are most likely consequences rather than primary causes of the disease. Most likely, chronic neurohumoral activation and abnormal mechanical load initiate the majority of the hitherto known changes in the myocardium and promote the further progression of cardiac failure as part of a vicious circle. Further extension of knowledge of pathophysiological mechanisms should improve therapeutical strategies which aim at slowing the progression of heart failure and at reversing secondary alterations by interrupting the deleterious influence of neurohumoral activation. Future progress will depend on answers to current gaps in our knowledge of heart failure, including the unknown primary cause of idiopathic dilated cardiomyopathy, factors underlying the greatly variable progression of pump failure, as well as the exact pathophysiological role of the molecular alterations as described in this review.

Publication Types:
  • Review
  • Review, Academic


PMID: 9798511 [PubMed - indexed for MEDLINE]

 
13: Cell 1993 Dec 3;75(5):977-84 Related Articles, OMIM, Books, LinkOut

Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro.

Sadoshima J, Xu Y, Slayter HS, Izumo S.

Molecular Medicine Division, Beth Israel Hospital, Boston, Massachusetts.

Hypertrophy is a fundamental adaptive process employed by postmitotic cardiac and skeletal muscle in response to mechanical load. How muscle cells convert mechanical stimuli into growth signals has been a long-standing question. Using an in vitro model of load (stretch)-induced cardiac hypertrophy, we demonstrate that mechanical stretch causes release of angiotensin II (Ang II) from cardiac myocytes and that Ang II acts as an initial mediator of the stretch-induced hypertrophic response. The results not only provide direct evidence for the autocrine mechanism in load-induced growth of cardiac muscle cells, but also define the pathophysiological role of the local (cardiac) renin-angiotensin system.

PMID: 8252633 [PubMed - indexed for MEDLINE]
 
14: N Engl J Med 1996 May 23;334(21):1349-55 Related Articles, Books, LinkOut

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The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group.

Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH.

Division of Circulatory Physiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

BACKGROUND. Controlled clinical trials have shown that beta-blockers can produce hemodynamic and symptomatic improvement in chronic heart failure, but the effect of these drugs on survival has not been determined. METHODS. We enrolled 1094 patients with chronic heart failure in a double-blind, placebo-controlled, stratified program, in which patients were assigned to one of the four treatment protocols on the basis of their exercise capacity. Within each of the four protocols patients with mild, moderate, or severe heart failure with left ventricular ejection fractions < or = 0.35 were randomly assigned to receive either placebo (n = 398) or the beta-blocker carvedilol (n = 696); background therapy with digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor remained constant. Patient were observed for the occurrence death or hospitalization for cardiovascular reasons during the following 6 months, after the beginning (12 months for the group with mild heart failure). RESULTS. The overall mortality rate was 7.8 percent in the placebo group and 3.2 percent in the carvedilol group; the reduction in risk attributable to carvedilol was 65 percent (95 percent confidence interval, 39 to 80 percent; P < 0.001). This finding led the Data and Safety Monitoring Board to recommend termination of the study before its scheduled completion. In addition, as compared with placebo, carvedilol therapy was accompanied by a 27 percent reduction in the risk of hospitalization for cardiovascular causes (19.6 percent vs. 14.1 percent, P = 0.036), as well as a 38 percent reduction in the combined risk of hospitalization or death (24.6 percent vs, 15.8 percent, P < 0.001). Worsening heart failure as an adverse reaction during treatment was less frequent in the carvedilol than in the placebo group. CONCLUSIONS. Carvedilol reduces the risk or death as well as the risk of hospitalization for cardiovascular causes in patients with heart failure who are receiving treatment with digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor.

Publication Types:

  • Clinical Trial
  • Randomized Controlled Trial


PMID: 8614419 [PubMed - indexed for MEDLINE]

 
15: Circulation 1994 Oct;90(4):1765-73 Related Articles, Books, LinkOut

Comment in:


A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees.

BACKGROUND: Functional benefit in heart failure due to idiopathic dilated cardiomyopathy has been observed after beta-blockade, but improvement in survival has not been established in a large-scale randomized trial. This was the main objective of the Cardiac Insufficiency Bisoprolol Study (CIBIS). METHODS AND RESULTS: Six hundred forty-one patients with chronic heart failure of various etiologies and a left ventricular ejection fraction of < 40% entered this placebo-controlled, randomized, double-blind study. Patients were in New York Heart Association functional class III (95%) or IV (5%) at inclusion. All received background diuretic and vasodilator therapy (an angiotensin-converting enzyme inhibitor in 90% of cases). A total of 320 patients was randomized to bisoprolol and 321 to placebo. Mean follow-up was 1.9 years. Bisoprolol was well tolerated without between group difference in premature treatment withdrawals (82 on placebo, 75 on bisoprolol; NS). The observed difference in mortality between groups did not reach statistical significance: 67 patients died on placebo, 53 on bisoprolol (P = .22; relative risk, 0.80; 95% confidence interval, 0.56 to 1.15). No significant difference was observed in sudden death rate (17 on placebo, 15 on bisoprolol) or death related to documented ventricular tachycardia or fibrillation (7 on placebo, 4 on bisoprolol). Bisoprolol significantly improved the functional status of the patients; fewer patients in the bisoprolol group required hospitalization for cardiac decompensation (90 on placebo versus 61 on bisoprolol, P < .01), and more patients improved by at least one New York Heart Association functional class (48 on placebo versus 68 on bisoprolol, P = .04) by the end of follow-up period. CONCLUSIONS: These results confirm previous trials evidence that a progressively increasing dose of beta-blocker in severe heart failure confers functional benefit. Subgroup analysis suggested that benefit from beta-blockade therapy was greater for those with nonischemic cardiomyopathy. However, improvement in survival while on beta-blockade remains to be demonstrated.

Publication Types:

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 7923660 [PubMed - indexed for MEDLINE]

 
16: Lancet 1999 Jun 12;353(9169):2001-7 Related Articles, Books, LinkOut

Comment in:

Click here to read
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)

BACKGROUND: Metoprolol can improve haemodynamics in chronic heart failure, but survival benefit has not been proven. We investigated whether metoprolol controlled release/extended release (CR/XL) once daily, in addition to standard therapy, would lower mortality in patients with decreased ejection fraction and symptoms of heart failure. METHODS: We enrolled 3991 patients with chronic heart failure in New York Heart Association (NYHA) functional class II-IV and with ejection fraction of 0.40 or less, stabilised with optimum standard therapy, in a double-blind randomised controlled study. Randomisation was preceded by a 2-week single-blind placebo run-in period. 1990 patients were randomly assigned metoprolol CR/XL 12.5 mg (NYHA III-IV) or 25.0 mg once daily (NYHA II) and 2001 were assigned placebo. The target dose was 200 mg once daily and doses were up-titrated over 8 weeks. Our primary endpoint was all-cause mortality, analysed by intention to treat. FINDINGS: The study was stopped early on the recommendation of the independent safety committee. Mean follow-up time was 1 year. All-cause mortality was lower in the metoprolol CR/XL group than in the placebo group (145 [7.2%, per patient-year of follow-up]) vs 217 deaths [11.0%], relative risk 0.66 [95% CI 0.53-0.81]; p=0.00009 or adjusted for interim analyses p=0.0062). There were fewer sudden deaths in the metoprolol CR/XL group than in the placebo group (79 vs 132, 0.59 [0.45-0.78]; p=0.0002) and deaths from worsening heart failure (30 vs 58, 0.51 [0.33-0.79]; p=0.0023). INTERPRETATION: Metoprolol CR/XL once daily in addition to optimum standard therapy improved survival. The drug was well tolerated.

Publication Types:

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 10376614 [PubMed - indexed for MEDLINE]

 
17: Eur Heart J 1998 Feb;19 Suppl B:B36-9 Related Articles, Books, LinkOut
Click here to read
Left ventricular remodelling and improved long-term outcomes in chronic heart failure.

Sharpe N, Doughty RN.

Department of Medicine, University of Auckland School of Medicine, New Zealand.

Several targets for heart failure therapy may be met through different mechanisms which are not necessarily associated. In the Australia/New Zealand Heart Failure Research Collaborative Group Study, patients with chronic stable heart failure of ischaemic aetiology on treatment including ACE inhibitors were randomized to treatment with either the vasodilator beta-blocking drug carvedilol or placebo. At 12 months, symptoms and exercise performance were unchanged, but ejection fraction increased significantly with carvedilol treatment; at 20 months, the rate of death and hospitalization was also significantly reduced in the carvedilol-treated group. In a sub-study using two dimensional echocardiography, progressive left ventricular (LV) dilatation occurred in the placebo group, compared with significant reductions in LV volumes with the carvedilol treatment group. An overview of all available carvedilol trial data showed the odds of death reduced by one-half with treatment (OR 0.51, 95% CI 0.33-0.77, 2P = 0.0014). Thus, improved LV remodelling occurs with carvedilol treatment in heart failure and is associated with improved long-term outcomes including survival. Improved LV function may, in part, mediate the survival benefit of carvedilol and provide a reliable surrogate for long-term outcomes.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 9519350 [PubMed - indexed for MEDLINE]

 
18: J Hypertens Suppl 1988 Dec;6(3):S7-12 Related Articles, Books, LinkOut

Molecular and physiological aspects of tissue renin-angiotensin system: emphasis on cardiovascular control.

Dzau VJ.

Division of Vascular Medicine and Atherosclerosis, Brigham and Women's Hospital, Boston, Massachusetts 02115.

Angiotensin II (Ang II), an important peptide in cardiovascular physiology, is the product of enzymatic processing of angiotensinogen which involves two proteolytic steps carried out by renin and angiotensin converting enzyme (ACE) sequentially. This system, which plays an important role in cardiorenal homeostasis, is conventionally considered an endocrine system. Increasing evidence supports the existence of this biochemical cascade in many tissues, in addition to its presence in the circulation. The molecular demonstration of tissue renin and angiotensinogen gene expressions suggest that the presence of this system is due, at least in part, to local synthesis. These observations have led to the hypothesis that locally generated angiotensin may be important in the regulation of individual tissue function, in addition to its circulating counterpart. This emerging concept may be important in providing an additional understanding of the role of renin angiotensin in cardiovascular physiology and in the response to pharmacological inhibitors of this system.

Publication Types:
  • Review
  • Review, Academic


PMID: 3066879 [PubMed - indexed for MEDLINE]

 
19: Cardiovasc Res 1993 Nov;27(11):1933-8 Related Articles, Books, LinkOut

Selective and time related activation of the cardiac renin-angiotensin system after experimental heart failure: relation to ventricular function and morphology.

Pinto YM, de Smet BG, van Gilst WH, Scholtens E, Monnink S, de Graeff PA, Wesseling H.

Department of Clinical Pharmacology, University of Groningen, The Netherlands.

OBJECTIVE: The cardiac renin-angiotensin system is activated in experimental heart failure, but it is unknown at what stage of heart failure it becomes activated, and whether activation is related to ventricular dysfunction and dilatation. Changes in activity of cardiac, renal, and plasma angiotensin converting enzyme (ACE) were therefore examined at different stages of experimental heart failure, with simultaneous measurements of left ventricular pressure, systolic dP/dt, and inner ventricular radius. METHODS: Heart failure was induced by experimental infarction in 17 normotensive male Wistar rats; 14 rats were sham operated. Rats were killed 3, 5, or 80 d after infarction. In an isolated heart perfusion, left ventricular pressure and systolic dP/dT were measured. ACE activity was determined in samples of the left and right cardiac ventricle, kidney, and plasma. Radius of the ventricular cavity was planimetrically determined in transverse sections of the left ventricle. RESULTS: At the different stages both left ventricular pressure and systolic dP/dT progressively decreased and inner radius of the left ventricle increased in all heart failure groups. ACE activity in the left ventricle increased significantly in all heart failure groups and correlated inversely with left ventricular pressure (R = -0.81; p < 0.001) and dP/dt (R = -0.85; p < 0.001). ACE activity in the kidney was only increased 80 d after the induction of heart failure [17(SEM 1) v 11.2(0.5) nM His-Leu generated per min.mg-1, p < 0.01], while plasma ACE activity was not increased in any heart failure group. CONCLUSIONS: Cardiac ACE is activated in the early stage after induction of heart failure and is related to the amount of dysfunction. ACE in the kidney is activated only in the chronic stage. The cardiac renin-angiotensin system therefore already appears to be an important neurohumoral adjustment in the early stage of heart failure and is thereby a suitable target for early intervention by ACE inhibitors.

PMID: 8287399 [PubMed - indexed for MEDLINE]
 
20: J Mol Cell Cardiol 1993 Feb;25(2):133-43 Related Articles, Books, LinkOut

Selective activation of cardiac angiotensinogen gene expression in post-infarction ventricular remodeling in the rat.

Lindpaintner K, Lu W, Neidermajer N, Schieffer B, Just H, Ganten D, Drexler H.

Department of Cardiology, Children's Hospital, Boston, MA 02115.

Recent studies in both experimental animals and man have demonstrated the unique efficacy of converting enzyme inhibitors to prevent or attenuate ventricular remodeling after myocardial infarction. Concomitantly, evidence for a trophic role of the renin-angiotensin system (RAS), as well as for the existence of an intracardiac tissue-resident RAS, has been presented, raising the question whether altered regulation of this cardiac RAS may be associated with the process of ventricular remodeling. We conducted the present study to examine whether cardiac angiotensinogen gene expression is altered after myocardial infarction. Experiments were performed in rats 5 and 25 days after ligation of the left coronary artery or sham operation. Coronary artery ligation resulted in relative infarct sizes averaging 29% and 36% of total left ventricular mass at 5 and 25 days and in marked elevations of left ventricular end-diastolic pressure (LVEDP). Angiotensinogen mRNA levels, measured by solution hybridization assay and confirmed in a second, independent experimental group by RNAse protection assay, were significantly elevated in the non-infarcted portion of the left ventricle at 5 days after infarction when compared to the sham group (22.1 + 3.3 vs. 13.4 +/- 2.0 fg/microgram total RNA; ratio of densitometric absorbance for angiotensinogen/beta-actin: 0.356 +/- 0.041 vs. 0.156 +/- 0.02), and showed a significant correlation with infarct size (r = 0.93). At 25 days, angiotensinogen gene expression had returned to control values. Similarly, no significant differences in angiotensinogen mRNA levels between animals with and without infarction were found in other cardiac tissues (atria, right ventricle). Plasma renin activity was significantly increased over baseline in the infarct group at 5, but not at 25 days. Our results demonstrate that acute hemodynamic embarrassment early after LV infarction is associated with augmented angiotensinogen gene expression. The potential significance of this finding is discussed.

PMID: 8474123 [PubMed - indexed for MEDLINE]
 
21: Circ Res 1993 Jun;72(6):1149-62 Related Articles, Books, LinkOut

Regulation of angiotensin II receptors on ventricular myocytes after myocardial infarction in rats.

Meggs LG, Coupet J, Huang H, Cheng W, Li P, Capasso JM, Homcy CJ, Anversa P.

Department of Medicine, New York Medical College, Valhalla 10595.

To determine the effects of acute myocardial infarction on the regulation of angiotensin II (Ang II) receptors and contractile performance of left and right ventricular myocytes, coronary artery ligation was surgically induced in rats, and Ang II receptor density and affinity and the mechanical properties of surviving muscle cells were examined 1 week later. Physiological determinations of cardiac pump function revealed the presence of ventricular failure, which was associated at the cellular level with a depression in the velocity of myocyte shortening and relengthening, a prolongation of time to peak shortening, and a reduction in the extent of cell shortening. These abnormalities in single-cell function were more prominent in left than in right ventricular myocytes. Cellular hypertrophy was documented by increases in cell length and width, which were also greater in the spared myocytes of the infarcted left ventricle. Reactive hypertrophy was accompanied by a 1.84- and 1.85-fold increase in the density of Ang II receptors on left and right myocytes, respectively. On the other hand, the affinity of Ang II receptors for the radiolabeled antagonist was not altered. However, Ang II-stimulated phosphoinositol turnover was enhanced by 3.7- and 2.5-fold in left and right myocytes, respectively, after infarction. Ventricular myocytes were found to possess the AT1 receptor subtype exclusively. In conclusion, myocardial infarction leads to impairment in the contractile behavior of the remaining cells and to the activation of Ang II receptors and effector pathway associated with these receptors, which may be involved in the reactive growth adaptation of the viable myocytes.

PMID: 8495545 [PubMed - indexed for MEDLINE]
 
22: Clin Exp Hypertens 1999 Jan-Feb;21(1-2):145-56 Related Articles, Books, LinkOut

Modification of cardiac subcellular remodeling due to pressure overload by captopril and losartan.

Liu X, Sentex E, Golfman L, Takeda S, Osada M, Dhalla NS.

Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Department of Physiology, University of Manitoba, Winnipeg, Canada.

In view of the activation of renin-angiotensin system under conditions associated with pressure overload on the heart, we examined the effects of captopril, an angiotensin converting enzyme inhibitor, and losartan, an angiotensin II receptor antagonist, on cardiac function, myofibrillar ATPase and sarcoplasmic reticular (SR) Ca2+-pump (SERCA2) activities, as well as myosin and SERCA2 gene expression in hypertrophied hearts. Cardiac hypertrophy was induced in rats treated with or without captopril or losartan by banding the abdominal aorta for 8 weeks; sham operated animals served as control. Decrease in left ventricular developed pressure, +dP/dt and -dP/dt as well as increase in left ventricular end diastolic pressure and increased muscle mass due to pressure overload were prevented by captopril or losartan. Treatment of animals with captopril or losartan also attenuated the pressure overload-induced depression in myofibrillar Ca2+-stimulated ATPase, myosin ATPase, SR Ca2+-uptake and SR Ca2+-release activities. An increase in beta-myosin heavy chain mRNA and a decrease in alpha-myosin heavy chain mRNA as well as depressed SERCA2 protein and SERCA2 mRNA levels were prevented by captopril or losartan. These results suggest that both captopril and losartan improve myocardial function in cardiac hypertrophy by preventing changes in gene expression and subsequent subcellular remodeling due to pressure overload.

PMID: 10052650 [PubMed - indexed for MEDLINE]
 
23: Lancet 1991 Apr 13;337(8746):872-6 Related Articles, Books, LinkOut

Erratum in:
  • Lancet 1991 May 11;337(8750):1174


Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin-converting-enzyme inhibition.

Sharpe N, Smith H, Murphy J, Greaves S, Hart H, Gamble G.

Department of Medicine, University of Auckland School of Medicine, Auckland Hospital, New Zealand.

Left ventricular dysfunction can be improved with angiotensin-converting-enzyme inhibition started 1 week after myocardial infarction or later. To see whether earlier intervention may confer greater benefit, a double-blind study was carried out in which 100 patients with Q wave myocardial infarction, but without clinical heart failure, were randomly allocated treatment with captopril 50 mg twice daily or placebo starting 24-48 h after onset of symptoms. Left ventricular volumes were measured regularly during 3 months of treatment and after a 48 h withdrawal period by means of two-dimensional echocardiography. The placebo group showed significant increases in left ventricular end-diastolic (LVEDVI) and end-systolic (LVESVI) volume indices, with the ejection fraction unchanged. By contrast, the captopril group showed a slight but not significant rise in LVEDVI and a significant reduction in LVESVI with ejection fraction increased significantly. At 3 months there was a 4.6% difference in the change in ejection fraction from baseline between the groups (p less than 0.0001). Most of the treatment benefit was evident at 1 month and there were no changes in left ventricular volumes after 48 h withdrawal of treatment at 3 months. Heart failure requiring treatment with frusemide developed in 7 patients in each group during the study period; 3 of these (1 captopril-treated, 2 placebo-treated) had to be withdrawn from the trial with severe heart failure requiring open treatment. Thus early treatment with captopril is effective in preventing the ventricular dilatation that can occur after Q wave myocardial infarction.

Publication Types:

  • Clinical Trial
  • Randomized Controlled Trial


PMID: 1672967 [PubMed - indexed for MEDLINE]

 
24: JAMA 1995 May 10;273(18):1450-6 Related Articles, Books, LinkOut

Erratum in:
  • JAMA 1995 Aug 9;274(6):462


Comment in:

  • ACP J Club. 1995 Nov-Dec;123(3):62


Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials.

Garg R, Yusuf S.

Clinical Trials Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.

OBJECTIVE--To evaluate the effect of angiotensin-converting enzyme (ACE) inhibitors on mortality and morbidity in patients with symptomatic congestive heart failure. DATA SOURCE AND STUDY SELECTION--Data were obtained for all completed, published or unpublished, randomized, placebo-controlled trials of ACE inhibitors that were at least 8 weeks in duration and had determined total mortality by intention to treat, regardless of sample size. Trials were identified based on literature review and correspondence with investigators and pharmaceutical firms. DATA EXTRACTION--Using standard tables, data were extracted by one author and confirmed where necessary by the other author or the principal investigator of the trial. Unpublished data were obtained by direct correspondence with the principal investigator of each study or pharmaceutical firm. DATA SYNTHESIS--The data for each outcome were combined using the Yusuf-Peto adaptation of the Mantel-Haenszel method. Overall, there was a statistically significant reduction in total mortality (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.67 to 0.88; P < .001) and in the combined endpoint of mortality or hospitalization for congestive heart failure (OR, 0.65; 95% CI, 0.57 to 0.74; P < .001). Similar benefits were observed with several different ACE inhibitors, although the data were largely based on enalapril maleate, captopril, ramipril, quinapril hydrochloride, and lisinopril. Reductions for total mortality and the combined endpoint were similar for various subgroups examined (age, sex, etiology, and New York Heart Association class). However, patients with the lowest ejection fraction appeared to have the greatest benefit. The greatest effect was seen during the first 3 months, but additional benefit was observed during further treatment. The reduction in mortality was primarily due to fewer deaths from progressive heart failure (OR, 0.69; 95% CI, 0.58 to 0.83); point estimates for effects on sudden or presumed arrhythmic deaths (OR, 0.91; 95% CI, 0.73 to 1.12) and fatal myocardial infarction (OR, 0.82; 95% CI, 0.60 to 1.11) were less than 1 but were not significant. CONCLUSIONS--Total mortality and hospitalization for congestive heart failure are significantly reduced by ACE inhibitors with consistent effects in a broad range of patients.

Publication Types:

  • Meta-Analysis


PMID: 7654275 [PubMed - indexed for MEDLINE]

 
25: Lancet 2000 May 6;355(9215):1575-81 Related Articles, Books, LinkOut

Comment in:

Click here to read
Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group.

Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, Torp-Pedersen C, Ball S, Pogue J, Moye L, Braunwald E.

Preventive Cardiology and Therapeutic Research Program, Hamilton Health Sciences Corporation Research Centre, McMaster University, Ontario, Canada.

BACKGROUND: We undertook a prospective systematic overview based on data from individual patients from five long-term randomised trials that assessed inhibitors of angiotensin-converting enzyme (ACE) in patients with left-ventricular dysfunction or heart failure. METHODS: Three of the trials enrolled patients within a week after acute myocardial infarction. Data were combined by use of the Peto-Yusuf method. FINDINGS: Overall 12,763 patients were randomly assigned treatment or placebo and followed up for an average of 35 months. In the three post-infarction trials (n=5,966), mortality was lower with ACE inhibitors than with placebo (702/2995 [23.4%] vs 866/2971 [29.1%]; odds ratio 0.74 [95% CI 0.66-0-83]), as were the rates of readmission for heart failure (355 [11.9%] vs 460 [15.5%]; 0.73 [0.63-0.85]), reinfarction (324 [10.8%] vs 391 [13.2%]; 0.80 [0.69-0.94]), or the composite of these events (1049 [35.0%] vs 1244 [41.9%]; 0.75 [0.67-0.83]; all p<O.001). For all five trials the ACE inhibitor group had lower rates of death than the placebo group (1,467/6,391 [23.0%] vs 1,710/6,372 [26.8%]; 0.80 [0.74-0.87]) and lower rates of reinfarction (571 [8.9%] vs 703 [11.0%]; 0.79 [0.70-0.89]), readmission for heart failure (876 [13.7%] vs 1202 [18.9%]; 0.67 [0.61-0.74]), and the composite of these events (2161 [33.8%] vs 2610 [41.0%]; 0.72 [0.67-0.78]; all p<0.0001). The benefits were observed early after the start of therapy and persisted long term. The benefits of treatment on all outcomes were independent of age, sex, and baseline use of diuretics, aspirin, and beta-blockers. Although there was a trend towards greater reduction in risk of death or readmission for heart failure in patients with lower ejection fractions, benefit was apparent over the range examined.

Publication Types:

  • Meta-Analysis


PMID: 10821360 [PubMed - indexed for MEDLINE]

26. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685–691.

 
27: Eur Heart J 1999 Jul;20(14):997-1008 Related Articles, Books, LinkOut

Erratum in:
  • Eur Heart J 1999 Dec;20(24):1846


Comment in:

Click here to read
AT1-receptor blockers in hypertension and heart failure: clinical experience and future directions.

Willenheimer R, Dahlof B, Rydberg E, Erhardt L.

Department of Cardiology, University Hospital Malmo, Lund University, Malmo, Sweden.

Publication Types:

  • Review
  • Review, Academic


PMID: 10381851 [PubMed - indexed for MEDLINE]

 
28: Lancet 2000 May 6;355(9215):1582-7 Related Articles, Books, LinkOut

Comment in:

Click here to read
Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial--the Losartan Heart Failure Survival Study ELITE II.

Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, Konstam MA, Riegger G, Klinger GH, Neaton J, Sharma D, Thiyagarajan B.

Division of Cardiology, University of Michigan School of Medicine, Ann Arbor 48109-0366, USA. b.pitt@umich.edu

BACKGROUND: The ELITE study showed an association between the angiotensin II antagonist losartan and an unexpected survival benefit in elderly heart-failure patients, compared with captopril, an angiotensin-converting-enzyme (ACE) inhibitor. We did the ELITE II Losartan Heart Failure Survival Study to confirm whether losartan is superior to captopril in improving survival and is better tolerated. METHODS: We undertook a double-blind, randomised, controlled trial of 3,152 patients aged 60 years or older with New York Heart Association class II-IV heart failure and ejection fraction of 40% or less. Patients, stratified for beta-blocker use, were randomly assigned losartan (n=1,578) titrated to 50 mg once daily or captopril (n=1,574) titrated to 50 mg three times daily. The primary and secondary endpoints were all-cause mortality, and sudden death or resuscitated arrest. We assessed safety and tolerability. Analysis was by intention to treat. FINDINGS: Median follow-up was 555 days. There were no significant differences in all-cause mortality (11.7 vs 10.4% average annual mortality rate) or sudden death or resuscitated arrests (9.0 vs 7.3%) between the two treatment groups (hazard ratios 1.13 [95.7% CI 0.95-1.35], p=0.16 and 1.25 [95% CI 0.98-1.60], p=0.08). Significantly fewer patients in the losartan group (excluding those who died) discontinued study treatment because of adverse effects (9.7 vs 14.7%, p<0.001), including cough (0.3 vs 2.7%).

Publication Types:

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 10821361 [PubMed - indexed for MEDLINE]

 
29: Cardiologia 1994 Dec;39(12 Suppl 1):389-93 Related Articles, Books, LinkOut

Myocardial collagen matrix remodeling and congestive heart failure.

Brilla CG, Rupp H.

Division of Cardiology, Philipps-University of Marburg, Germany.

In chronic heart failure, the inter-relationship of the renin-angiotensin-aldosterone system (RAAS) and cardiac growth is of primary clinical interest. In the pressure or volume overloaded heart, hypertrophic growth of the myocardium includes the enlargement of cardiac myocytes--an adaptation governed by ventricular loading. Nonmyocyte cell growth involving cardiac fibroblast may also occur but not primarily regulated by the hemodynamic load. Cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium and adventitia of intramyocardial coronary arteries. In addition to relaxation abnormalities due to impairment of sarcoplasmic Ca(2+)-ATPase activity, this remodeling of the cardiac interstitium represents a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness, leading to ventricular diastolic and systolic dysfunction and ultimately the appearance of symptomatic heart failure. In vivo and in vitro studies suggest that the effector hormones, angiotensin II and aldosterone, of the RAAS are primarily involved in regulating the structural remodeling of the myocardial collagen matrix. In cultured adult cardiac fibroblasts, angiotensin II and aldosterone have been shown to stimulate collagen synthesis while angiotensin II additionally inhibits matrix metalloproteinase 1 activity, which is the key enzyme for interstitial collagen degradation in the myocardium. These observations may serve as rationale why angiotensin converting enzyme inhibition or blockade of the RAAS represents such remedial therapy in congestive heart failure in patients with hypertensive heart disease, post-myocardial infarction or with dilated cardiomyopathy.

PMID: 7634301 [PubMed - indexed for MEDLINE]
 
30: N Engl J Med 1999 Sep 2;341(10):709-17 Related Articles, Books, LinkOut

Comment in:

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The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.

Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J.

Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, USA.

BACKGROUND AND METHODS: Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes. RESULTS: The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients. CONCLUSIONS: Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure.

Publication Types:

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 10471456 [PubMed - indexed for MEDLINE]

 
31: Circulation 1996 Mar 15;93(6):1214-22 Related Articles, Books, LinkOut

Comment in:

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Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure. Marked increase in endothelin-1 production in the failing heart.

Sakai S, Miyauchi T, Sakurai T, Kasuya Y, Ihara M, Yamaguchi I, Goto K, Sugishita Y.

Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Japan.

BACKGROUND: Although it was demonstrated that circulating endothelin-1 (ET-1) levels are elevated in congestive heart failure (CHF), the production and roles of ET-1 in the failing heart are not known. We investigated the production of ET-1 in the heart and the density of myocardial ET receptors in rats with CHF. We also investigated the effects of intravenously infused BQ-123, an endothelin(A) (ETA) receptor antagonist, on both heart and myocardial contractility in rats with CHF. METHODS AND RESULTS: We used the left coronary artery-ligated rat model of CHF (CHF rats). Three weeks after surgery, the rats developed CHF. Plasma ET-1 concentration was significantly higher in the CHF rats than in the sham-operated rats (P<.01). In the left ventricle, the expression prepro-ET-1 mRNA was markedly higher in the CHF rats than in the sham-operated rats. The peptide level of ET-1 in the left ventricle was also significantly higher in the CHF rats than in the sham-operated rats (500+/-41 versus 102+/-10 pg/g tissue, P<.01). Myocardial ET receptors were significantly higher in the CHF rats than in the sham-operated rats (243+/-20 versus 155+/-17 fmol/mg protein, P<.05). In the CHF rats, intravenous BQ-123 infusion (0.1 mg x kg(-1) x min(-1) for 120 minutes) significantly decreased both heart rate (P<.01) and LV+dP x dt(max) (P<.05) but not mean blood pressure. BQ-123 infusion did not affect these hemodynamic parameters in the sham-operated rats. CONCLUSIONS: In the present study, we demonstrated that the production of ET-1 in the heart is markedly increased and that the density of myocardial ET receptors is significantly elevated in the CHF rats. Intravenous BQ-123 infusion significantly reduced both heart rate and LV+dP/dt(max) in the CHF rats but not in the sham-operated rats. Therefore, the ET receptor-mediated signal transduction system in the heart appears to be markedly stimulated in the CHF rats, and endogenous ET-1 may be involved in the maintenance of the cardiac function in these rats.

PMID: 8653844 [PubMed - indexed for MEDLINE]

 
32: Cardiovasc Res 1993 Dec;27(12):2130-4 Related Articles, Books, LinkOut

Effects of endothelins on collagen turnover in cardiac fibroblasts.

Guarda E, Katwa LC, Myers PR, Tyagi SC, Weber KT.

Department of Internal Medicine, University of Missouri-Columbia 65212.

OBJECTIVES: Endothelins (ET-1 and ET-3) may be promoters of tissue remodeling, including fibrillar collagen accumulation. The hypothesis that ET-1 and ET-3 each modify cardiac fibroblast collagen turnover was tested. METHODS: Confluent adult rat cardiac fibroblasts were maintained for 24 hours in medium with 0.4% fetal calf serum, and varying concentrations of ET-1 or ET-3. Collagen synthesis was measured by 3H-proline incorporation. The synthesis of type I and III collagens was measured by enzyme linked immunosorbent assay (ELISA). The effects of endothelins on collagenase activity were estimated by zymography. RESULTS: ET-1 and ET-3 increased collagen synthesis in a concentration-dependent manner with a maximal 1.7-fold increase (p < 0.001 v control cells). The effects of ET-1 or ET-3 on collagen synthesis were not blocked by PED-3512-PI (10(-6) M), an ETA receptor antagonist. ET-1 and ET-3 each significantly (p < 0.01) increased the synthesis of both type I and III collagens. ET-1 caused a 5.8-fold decrease in collagenase activity (p < 0.01 v control), and this effect was blocked by PED-3512-PI (10(-6) M). ET-3 did not alter collagenase activity. CONCLUSION: ET-1 and ET-3 increased the synthesis of type I and III collagens, whereas ET-1, but not ET-3, reduced collagenase activity. The effects of endothelins on collagen synthesis in cardiac fibroblasts seem to be mediated through ETA and ETB receptors, whereas their effects on collagenase seem to be mediated by ETA receptors.

PMID: 8313419 [PubMed - indexed for MEDLINE]
 
33: Biochim Biophys Acta 1993 Feb 17;1175(3):327-32 Related Articles, Books, LinkOut

Stimulation of adult rat ventricular myocyte protein synthesis and phosphoinositide hydrolysis by the endothelins.

Sugden PH, Fuller SJ, Mynett JR, Hatchett RJ 4th, Bogoyevitch MA, Sugden MC.

Department of Cardiac Medicine, National Heart and Lung Institute, University of London, UK.

The effects of endothelin-1 (ET-1) on protein synthesis and phosphoinositide (PI) hydrolysis were investigated in ventricular myocytes isolated by collagenase digestion of adult rat hearts. The maximum stimulation of protein synthesis by ET-1 was about 35% and the EC50 value was about 0.3 nM. The stimulation was exerted at the translational stage since it was insensitive to inhibition by actinomycin D. The maximum stimulation of PI hydrolysis by ET-1 as measured by the formation of [3H]inositol phosphates was about 11-fold and the EC50 value was about 0.7 nM. The ET-1 analogue sarafotoxin-6b stimulated protein synthesis by a maximum of 27% and stimulated PI hydrolysis about 8- to 9-fold. The EC50 values were 1.6 nM and 0.6 nM, respectively. Other endothelins stimulated protein synthesis and PI hydrolysis in the following order of potency: ET-1 approximately ET-2 > ET-3. This order of potency suggests that the stimulation of both protein synthesis and PI hydrolysis is mediated through the ETA receptor. Although both angiotensin II and [Arg]vasopressin stimulated PI hydrolysis significantly, the stimulation was less than 60%, i.e., much less than the stimulation by ET-1 and its analogues. Neither insulin nor substance P stimulated PI hydrolysis. Stimulation of protein synthesis by ET-1 and its analogues correlated strongly with the stimulation of PI hydrolysis and we suggest that the stimulation of protein synthesis may be dependent on the stimulation of PI hydrolysis. We hypothesize that the mechanism may involve a protein kinase C-mediated increase in intracellular pH.

PMID: 8382085 [PubMed - indexed for MEDLINE]
 
34: Circulation 1997 Sep 16;96(6):1976-82 Related Articles, Books, LinkOut
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Role of endogenous endothelin in chronic heart failure: effect of long-term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling.

Mulder P, Richard V, Derumeaux G, Hogie M, Henry JP, Lallemand F, Compagnon P, Mace B, Comoy E, Letac B, Thuillez C.

VACOMED, Department of Pharmacology, Rouen University Medical School and Rouen University Hospital, France.

BACKGROUND: Plasma levels of the vasoconstrictor peptide endothelin (ET) are increased in chronic heart failure (CHF), and ET levels are a major predictor of mortality in this disease. Thus, ET may play a deleterious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a rat model of CHF. METHODS AND RESULTS: Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg x kg(-1) x d(-1)). Bosentan 100 mg x kg(-1) markedly increased survival (after 9 months: untreated, 47%; bosentan, 65%; P<.01). Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate. After 2 or 9 months of treatment, the ET antagonist reduced central venous pressure and left ventricular (LV) end-diastolic pressure as well as plasma catecholamines, urinary cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume relationship ex vivo). Echocardiographic studies performed after 2 months showed that the ET antagonist reduced hypertrophy and increased contractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg x kg(-1)), which had no major hemodynamic or structural effects, also had no effect on survival. CONCLUSIONS: Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.

PMID: 9323089 [PubMed - indexed for MEDLINE]
 
35: J Card Fail 2000 Dec;6(4):359-68 Related Articles, Books, LinkOut
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New developments in heart failure: role of endothelin and the use of endothelin receptor antagonists.

Suresh DP, Lamba S, Abraham WT.

Division of Cardiology, University of Cincinnati College of Medicine, Ohio, USA.

Despite conventional therapy, there is still much room for improvement in the prognosis of patients with chronic systolic heart failure. Evidence supports a role for endothelin-1 (ET-1), a potent vasoconstrictor, in the pathophysiology of heart failure. Given its potentially deleterious effects, the optimal treatment of heart failure may need to include efforts directed toward antagonizing this hormone. In support of this notion, the use of ET receptor antagonists produces a number of beneficial effects in heart failure, including both improvements in hemodynamics and reductions in the levels of other vasoconstricting neurohormones. There are at least 2 receptors for ET-1 (the ET-A and ET-B receptor), and the effects of ET-1 binding differ depending on the receptor involved. It is still unclear whether blockade of the ET-A receptor alone or the combined blockade of both the ET-A and ET-B receptors will be most efficacious as a therapeutic strategy. Long-term benefits have been achieved with the use of a mixed ET-A/B receptor antagonist, when added to standard triple-drug therapy, in patients with severe heart failure. We await the results of ongoing trials to determine if these agents will fulfill the promise of adding substantial incremental benefit to the treatment of the disease.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 11145761 [PubMed - indexed for MEDLINE]

 
36: Circulation 2001 Feb 20;103(7):973-80 Related Articles, Books, LinkOut
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Hemodynamic effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with class III to IV congestive heart failure.

Torre-Amione G, Young JB, Durand J, Bozkurt B, Mann DL, Kobrin I, Pratt CM.

Winters Center for Heart Failure Research, the Eugene and Judith Campbell Laboratories for Cardiac Transplantation Research, Houston, Texas, USA. gtorre@bcm.tmc.edu

BACKGROUND: Endothelin-1, a powerful mediator of vasoconstriction, is increased in patients with congestive heart failure and appears to be a prognostic marker that strongly is correlated with the severity of disease. However, little is known about the potential immediate beneficial effects of acute blockade of the endothelin system in patients with symptomatic left ventricular dysfunction. We assessed the hemodynamic effects and safety of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with moderate to severe heart failure. METHODS AND RESULTS: This randomized placebo-controlled study evaluated the hemodynamic effects of 6-hour infusions of tezosentan at 5, 20, 50, and 100 mg/h compared with placebo in 61 patients with New York Heart Association class III to IV heart failure. Plasma endothelin-1 and tezosentan concentrations were also determined. Treatment with tezosentan caused a dose-dependent increase in cardiac index ranging from 24.4% to 49.9% versus 3.0% with placebo. Tezosentan also dose-dependently reduced pulmonary capillary wedge pressure and pulmonary and systemic vascular resistances, with no change in heart rate. No episodes of ventricular tachycardia or hypotension requiring drug termination were observed during tezosentan infusion. Tezosentan administration resulted in dose-related increased plasma endothelin-1 concentrations. CONCLUSIONS: The present study demonstrated that tezosentan can be safely administered to patients with moderate to severe heart failure and that by virtue of its ability to antagonize the effects of endothelin-1, it induced vasodilatory responses leading to a significant improvement in cardiac index. Further studies are under way to determine the clinical effects of tezosentan in the setting of acute heart failure.

Publication Types:
  • Clinical Trial
  • Randomized Controlled Trial


PMID: 11181472 [PubMed - indexed for MEDLINE]

 
37 : Eur Heart J 1998 Feb;19 Suppl B:B19-24 Related Articles, Books, LinkOut
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Carvedilol: preclinical profile and mechanisms of action in preventing the progression of congestive heart failure.

Ruffolo RR Jr, Feuerstein GZ.

Division of Pharmacological Sciences, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939, USA.

Many pathophysiological processes are activated in patients with congestive heart failure, and several of these have been implicated in the progression of the disease. The most important processes to be activated in heart failure are the neurohormonal systems, which include the reninangiotensin system, the sympathetic nervous system and the endothelin system. In addition to the neurohormonal systems, the formation of reactive oxygen free radicals is increased in congestive heart failure. It has been proposed that the activation of neurohormonal pathways and the formation of oxygen free radicals ultimately lead to the activation of a family of transcription factors that are involved in cardiac and vascular remodelling which are hallmarks of congestive heart failure. In addition, the formation of oxygen free radicals has been implicated in the process of apoptosis, or programmed cell death, which may contribute to the continued loss of myocardial cells resulting in progressive decreases in left ventricular function, while at the same time contributing to the cardiac remodelling process which subsequently creates a pro-arrhythmic environment in the myocardium. Carvedilol is a novel multiple-action neurohormonal antagonist that has been shown to be effective in the management of congestive heart failure. Carvedilol also possesses a number of additional activities which may inhibit many of the chronic pathophysiological processes that are involved in the progression of congestive heart failure.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 9519348 [PubMed - indexed for MEDLINE]

 
38: J Am Coll Cardiol 1996 Apr;27(5):1201-6 Related Articles, Books, LinkOut
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Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD).

Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL.

Department of Medicine, Veterans Administration Medical Center and Baylor College of Medicine, Houston, Texas, USA.

OBJECTIVES. This study sought to assess proinflammatory cytokine levels in patients in the studies of left ventricular dysfunction trial (SOLVD) in relation to both their New York Heart Association functional classification and their neurohormonal status before randomization. BACKGROUND. Elevated levels of tumor necrosis factor-alpha have been identified in 30% to 40% of patients with heart failure. However, it is unclear which subsets of patients with heart failure elaborate tumor necrosis factor-alpha. It is also unclear what the mechanism for the increased expression of proinflammatory cytokines is. METHODS. Tumor necrosis factor-alpha and interleukin-6 levels were analyzed by enzymes-linked immunoassay using randomly selected plasma samples from patients in functional classes I to III who were enrolled in neurohormonal substudies of the SOLVD trial; age-matched healthy subjects served as the control group. RESULTS. Plasma levels of tumor necrosis factor-alpha (p < 0.001) were elevated in patients in functional classes I to III ([mean +/- SD] 1.95 +/- 0.54, 2.63 +/- 0.48, 6.4 +/- 1.9 pg/ml, respectively) compared with age-matched control subjects (0.75 +/- 0.05 pg/ml) and were progressively elevated in relation to decreasing functional status of the patient. Plasma levels of interleukin-6 (p < 0.001) were elevated in patients in functional classes I to III (3.3 +/- 0.55, 6.2 +/- 1.1, 5.22 +/- 0.9 pg/ml, respectively) compared with age-matched control subjects (1.8 +/- 0.5 pg/ml and were progressively elevated in relation to decreasing functional status of the patient. Cox proportional-hazards analysis showed that there was a trend toward significance between plasma tumor necrosis factor-alpha (p < 0.07) and survival, whereas there was no significant relation for plasma interleukin-6 (p < 0.72). Except for atrial natriuretic factor, which correlated weakly (r = 0.23, p = 0.04) with circulating tumor necrosis factor-alpha levels, there was no significance correlation between neurohormonal and proinflammatory cytokine levels. CONCLUSIONS. Circulating levels of proinflammatory cytokines increase in patients as their functional heart failure classification deteriorates. Moreover, activation of the neurohumoral axis is unlikely to completely explain the elaboration of proinflammatory cytokines in heart failure.

Publication Types:
  • Clinical Trial
  • Randomized Controlled Trial


PMID: 8609343 [PubMed - indexed for MEDLINE]

 
39: J Clin Invest 1996 Dec 15;98(12):2854-65 Related Articles, Books, LinkOut
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Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death.

Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL, Glembotski CC, Quintana PJ, Sabbadini RA.

Department of Biology, San Diego State University, California 92182, USA.

In the present study, it was shown that physiologically relevant levels of the proinflammatory cytokine TNFalpha induced apoptosis in rat cardiomyocytes in vitro, as quantified by single cell microgel electrophoresis of nuclei ("cardiac comets") as well as by morphological and biochemical criteria. It was also shown that TNFalpha stimulated production of the endogenous second messenger, sphingosine, suggesting sphingolipid involvement in TNFalpha-mediated cardiomyocyte apoptosis. Consistent with this hypothesis, sphingosine strongly induced cardiomyocyte apoptosis. The ability of the appropriate stimulus to drive cardiomyocytes into apoptosis indicated that these cells were primed for apoptosis and were susceptible to clinically relevant apoptotic triggers, such as TNFalpha. These findings suggest that the elevated TNFalpha levels seen in a variety of clinical conditions, including sepsis and ischemic myocardial disorders, may contribute to TNFalpha-induced cardiac cell death. Cardiomyocyte apoptosis is also discussed in terms of its potential beneficial role in limiting the area of cardiac cell involvement as a consequence of myocardial infarction, viral infection, and primary cardiac tumors.

PMID: 8981934 [PubMed - indexed for MEDLINE]
 
40: Drugs 2000 Apr;59(4):745-51 Related Articles, Books, LinkOut

Role of tumour necrosis factor-alpha in the progression of heart failure: therapeutic implications.

Torre-Amione G, Vooletich MT, Farmer JA.

The Winters Center for Heart Failure Research, Baylor College of Medicine, Houston, Texas 77030, USA. azamora@bcm.tmc.edu

The experimental and clinical evidence that demonstrates the effect of various cytokines, and in particular tumour necrosis factor (TNF)alpha, in patients with heart failure continues to accumulate. It is well established that increased levels of TNFalpha appear in the circulation of patients with heart failure and that the levels may have prognostic significance. Also, increased circulating TNFalpha levels may be responsible for the decreased expression of myocardial TNF receptors observed in failing myocardium. Along with these clinical data, it has been clearly demonstrated that increased levels of TNFalpha lead to cardiomyopathy and eventually death in experimental animals. Therefore, it is reasonable to assume that the increased levels of TNFalpha in patients with heart failure may be detrimental to cardiac function. The hypothesis that TNFalpha contributes to the pathogenesis of heart failure has recently been tested at the clinical level. The results of specific TNFalpha antagonism in patients with symptomatic heart failure demonstrate that anti-TNFalpha therapy is well tolerated and may be effective. This hypothesis is currently being tested in a large randomised, multicentre study that is expected to be complete within the next 2 years. Perhaps the most important aspect of the evolving research into the role of cytokines in heart failure is that the recognition of activation of inflammatory mediators provides new targets for therapeutic intervention.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 10804032 [PubMed - indexed for MEDLINE]

 
41: Circulation 2001 Feb 27;103(8):1044-7 Related Articles, Books, LinkOut
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Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure.

Bozkurt B, Torre-Amione G, Warren MS, Whitmore J, Soran OZ, Feldman AM, Mann DL.

Winters Center For Heart Failure Research, Department of Medicine, Veterans Administration Medical Center, Houston, TX 77030, USA.

BACKGROUND: Previously, we showed that tumor necrosis factor (TNF) antagonism with etanercept, a soluble TNF receptor, was well tolerated and that it suppressed circulating levels of biologically active TNF for 14 days in patients with moderate heart failure. However, the effects of sustained TNF antagonism in heart failure are not known. METHODS AND RESULTS: We conducted a randomized, double-blind, placebo-controlled, multidose trial of etanercept in 47 patients with NYHA class III to IV heart failure. Patients were treated with biweekly subcutaneous injections of etanercept 5 mg/m(2) (n=16) or 12 mg/m(2) (n=15) or with placebo (n=16) for 3 months. Doses of 5 and 12 mg/m(2) etanercept were safe and well tolerated for 3 months. Treatment with etanercept led to a significant dose-dependent improvement in left ventricular (LV) ejection fraction and LV remodeling, and there was a trend toward an improvement in patient functional status, as determined by clinical composite score. CONCLUSION: Treatment with etanercept for 3 months was safe and well-tolerated in patients with advanced heart failure, and it resulted in a significant dose-dependent improvement in LV structure and function and a trend toward improvement in patient functional status.

Publication Types:
  • Clinical Trial
  • Randomized Controlled Trial


PMID: 11222463 [PubMed - indexed for MEDLINE]

 
42: J Clin Invest 1990 Feb;85(2):507-14 Related Articles, Books, LinkOut

Peptide growth factors can provoke "fetal" contractile protein gene expression in rat cardiac myocytes.

Parker TG, Packer SE, Schneider MD.

Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.

Cardiac-specific gene expression is intricately regulated in response to developmental, hormonal, and hemodynamic stimuli. To test whether cardiac muscle might be a target for regulation by peptide growth factors, the effect of three growth factors on the actin and myosin gene families was investigated by Northern blot analysis in cultured neonatal rat cardiac myocytes. Transforming growth factor-beta 1 (TGF beta 1, 1 ng/ml) and basic fibroblast growth factor (FGF, 25 ng/ml) elicited changes corresponding to those induced by hemodynamic load. The "fetal" beta-myosin heavy chain (MHC) was up-regulated about four-fold, whereas the "adult" alpha MHC was inhibited greater than 50-60%; expression of alpha-skeletal actin increased approximately two-fold, with little or no change in alpha-cardiac actin. Thus, peptide growth factors alter the program of differentiated gene expression in cardiac myocytes, and are sufficient to provoke fetal contractile protein gene expression, characteristic of pressure-overload hypertrophy. Acidic FGF (25 ng/ml) produced seven- to eightfold reciprocal changes in MHC expression but, unlike either TGF-beta 1 or basic FGF, inhibited both striated alpha-actin genes by 70-90%. Expression of vascular smooth muscle alpha-actin, the earliest alpha-actin induced during cardiac myogenesis, was increased by all three growth factors. Thus, three alpha-actin genes demonstrate distinct responses to acidic vs. basic FGF.

PMID: 1688886 [PubMed - indexed for MEDLINE]
 
43: Lancet 2000 Jun 10;355(9220):2012-3 Related Articles, Books, LinkOut

Comment in:

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Dressing heart-failure patients on Savile Row--tailored treatment?

Willenheimer R, Swedberg K.

Department of Cardiology, University Hospital, Malmo, Sweden.

PMID: 10885349 [PubMed - indexed for MEDLINE]

 
44: N Engl J Med 2000 Jan 20;342(3):145-53 Related Articles, Books, LinkOut

Erratum in:
  • 2000 May 4;342(18):1376
  • N Engl J Med 2000 Mar 9;342(10):748


Comment in:

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Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.

Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G.

Canadian Cardiovascular Collaboration Project Office, Hamilton General Hospital, McMaster University, ON. hope@ccc.mcmaster.ca

BACKGROUND: Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction, whether or not they have heart failure. We assessed the role of an angiotensin-converting-enzyme inhibitor, ramipril, in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure. METHODS: A total of 9297 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were randomly assigned to receive ramipril (10 mg once per day orally) or matching placebo for a mean of five years. The primary outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper. RESULTS: A total of 651 patients who were assigned to receive ramipril (14.0 percent) reached the primary end point, as compared with 826 patients who were assigned to receive placebo (17.8 percent) (relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001). Treatment with ramipril reduced the rates of death from cardiovascular causes (6.1 percent, as compared with 8.1 percent in the placebo group; relative risk, 0.74; P<0.001), myocardial infarction (9.9 percent vs. 12.3 percent; relative risk, 0.80; P<0.001), stroke (3.4 percent vs. 4.9 percent; relative risk, 0.68; P<0.001), death from any cause (10.4 percent vs. 12.2 percent; relative risk, 0.84; P=0.005), revascularization procedures (16.3 percent vs. 18.8 percent; relative risk, 0.85; P<0.001), cardiac arrest (0.8 percent vs. 1.3 percent; relative risk, 0.62; P=0.02), [corrected] heart failure (9.1 percent vs. 11.6 percent; relative risk, 0.77; P<0.001), and complications related to diabetes (6.4 percent vs. 7.6 percent; relative risk, 0.84; P=0.03). CONCLUSIONS: Ramipril significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure.

Publication Types:

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 10639539 [PubMed - indexed for MEDLINE]

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