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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

The cell and molecular biology of right ventricular dysfunction in pulmonary hypertension

Sheila G. Haworth

Developmental Cardiology, Institute of Child Health, University College London, London, UK and Department of Paediatric Cardiology, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK

Corresponding author. Tel: +44 207 405 9200.E-mail address: s.haworth{at}ich.ucl.ac.uk


   Abstract
Top
 Abstract
Introduction
 Bioenergetics of the right...
 Remodelling of the right...
 Reversible remodelling of the...
 References
 
Pulmonary vascular disease is accompanied by structural remodelling and dysfunction of the right ventricle. Current non-invasive studies describe the global performance of the right ventricle but do not explain the cell and molecular abnormalities which we need to understand if we are to develop therapeutic strategies to improve right ventricular function. This review attempt to summarise current opinion and in doing so emphasises the paucity of information specific to this ventricle.

Key Words: Right ventricle • Pulmonary hypertension • Ventricular remodelling


   Introduction
Top
 Abstract
 Introduction
Bioenergetics of the right...
 Remodelling of the right...
 Reversible remodelling of the...
 References
 
Pulmonary vascular disease and a progressive increase in pulmonary vascular resistance (PVR) are accompanied by structural remodelling and dysfunction of the right ventricle. Thus far, research has focused on the pulmonary vasculature in an attempt to understand and treat the underlying disorder, but maintaining right ventricular function is paramount in maintaining well-being and survival. With few exceptions, research in humans has understandably been restricted to non-invasive assessment of right ventricular function using echocardiography and magnetic resonance imaging. This approach describes the global performance of the ventricle, but does not address the cellular and biochemical response to an elevated PVR that we need to understand if we are to develop therapeutic strategies to improve right ventricular function. Non-invasive methods of assessing right ventricular compromise at cellular level are, however, developing rapidly. Right ventricular energy reserves can be assessed using magnetic resonance spectroscopy (MRS). Measuring the circulating levels of vasoactive mediators and natriuretic peptides gives clues about possible therapeutic interventions and not merely act as biomarkers of disease progression. Experimental studies on heart failure are shifting from a morphological to a functional bias utilizing gene-targeting strategies.

The cell and molecular biology of ventricular dysfunction has usually addressed left ventricular dysfunction, but some of the abnormalities described almost certainly apply to both ventricles. These include myocyte hypertrophy and apoptosis, phenotypic changes with re-expression of foetal genotypes, remodelling of the extracellular matrix, abnormalities in endothelin (ET) and nitric oxide systems, natriuretic peptides, inflammatory cytokines, and oxidative stress, all of which can contribute to remodelling the compromised right ventricle. Given the paucity of information about the cell and molecular changes occurring in the compromised right ventricle, this review frequently seeks parallels with changes occurring in the compromised left ventricle about which more is understood. There are, however, important functional differences between the ventricles, and the ventricles are inter-dependent. Therefore, it is necessary to issue a note of caution when extrapolating from one ventricle to another.


   Bioenergetics of the right ventricle
Top
 Abstract
 Introduction
 Bioenergetics of the right...
Remodelling of the right...
 Reversible remodelling of the...
 References
 
Magnetic resonance spectroscopy is a powerful non-invasive tool with which the relation between energy provision and energy expenditure in the myocardium is investigated. 31P-NMR spectroscopy has shown that left ventricular failure is associated with a reduction in phosphocreatine to adenosine (PCr/ATP) ratio.1 Abnormalities in high-energy phosphate metabolism in cardiomyopathy and valvular heart disease have been related to the severity of heart failure and, more recently, to echocardiographic indices of left ventricular dysfunction in patients with chronic mitral regurgitiation.2 The PCr/ATP ratio decreased as left ventricular dilatation increased. The reduced energy efficiency in heart failure is inversely correlated with the free fatty acid concentration and this, in turn, is associated with an increase in cardiac mitochondrial uncoupling proteins and a reduction in glucose transporter protein.3 Thus, energy deficiency in heart failure might be caused by less efficient ATP synthesis and reduced glucose uptake.

Those of us caring for patients with pulmonary hypertension have been slow to exploit the potential of NMR technique in studying right ventricular function. In 1996, Miall-Allen et al.4 studied babies as young as 5 months and children with congenital heart disease without any technical difficulty, interrogating the hypertrophied right ventricle that lay immediately above the surface coil in the prone child. The failing, hypertrophied systemic right ventricles of children with transposition of the great arteries had abnormally low PCr/ATP ratios. Recently, Spindler et al.5 used 31P-NMR in adults with pulmonary arterial hypertension (PAH) to describe the functional and metabolic recovery of the right ventricle in response to treatment with Bosentan.

Thus, NMR monitoring of high-energy phosphate metabolism may offer a precise method of assessing right ventricular failure and the response to treatment. It can be used to assess response to treatments directed both to the pulmonary vasculature and to the myocardium itself, specifically to increase myocardial energy reserves. Growth hormone and selective β-1 blockade improve myocardial energy metabolism in the post-infarct rat model, increasing the PCr/ATP ratio.6,7 Manipulating and restoring right ventricular energy reserves must be an important therapeutic goal. It has been postulated that a metabolic vicious circle is established in heart failure, sustained by adrenergic activation, in which an increase in circulating free fatty acids leads to energy wastage, as noted above.8 Drugs which reduce fatty acid metabolism and increase glucose metabolism might help. Studies using C-11 acetate kinetics measured using positron emission tomography suggest that β-blockade can have a beneficial effect on the metabolic cost of work, reducing oxidative metabolism in left ventricular dysfunction.9 Greater sensitivity may be achievable using spectral localisation with optimal pointspread function rather than conventional chemical shift imaging to obtain better spatial resolution.10

In conclusion, the evidence indicates that impaired energy efficiency accompanies right ventricular hypertrophy and remodelling, presumably making its impact all the more disastrous. Magnetic resonance spectroscopy almost certainly has the potential to project survival time and hence time to transplantation.

Magnetic resonance spectroscopy is also used to study skeletal muscle metabolism, important in a disease in which the primary end-point of all clinical drug trials has been the 6 min walk test, which it is assumed accurately reflects cardiac performance and is even a surrogate for cardiac output. This assumption assumes that skeletal muscle metabolism is normal, but this is not so in all patients with PAH. The skeletal muscle of hypoxaemic children with a right to left shunt, as in the Eisenmenger syndrome, has an abnormally high intracellular pH, energy reserves are readily depleted on exercise, and phosphocreatine resynthesis is abnormally slow on recovery from exercise, reflecting a low rate of mitochondrial ATP synthesis.11 Skeletal muscle abnormalities occur also in left ventricular dysfunction. The initial rate of ATP turnover is increased in established left heart failure.12 It is increased in the first 3 weeks following infarction, and the maximum rate of oxidative ATP synthesis is abnormally low in established heart failure 6 months after infarction. Skeletal muscle metabolism requires investigation in patients with PAH who are, and are not hypoxaemic.


   Remodelling of the right ventricle
Top
 Abstract
 Introduction
 Bioenergetics of the right...
 Remodelling of the right...
Reversible remodelling of the...
 References
 
Sustained pulmonary hypertension causes right ventricular dilatation and hypertrophy. The interventricular septum is flattened, moves with the right rather than the left ventricle, and the right ventricle becomes more globular and compresses the left ventricle. Right ventricular hypertrophy encompasses myocyte hypertrophy and apoptosis, changes in sarcolemmal and contractile proteins, altered calcium homeostasis, a shift in gene expression, and extracellular matrix remodelling. Much of what follows has been investigated in left ventricular myocytes and the extent to which it is applicable to right ventricular myocytes must be established.

Myocyte hypertrophy, phenotype, and apoptosis in the remodelled ventricle
Myocyte hypertrophy is evidenced by an increased protein synthesis without cell replication. It is stimulated by stretch, noradrenaline, ET, angiotensin, and inflammatory cytokines such as interleukin-1b, all of which are thought to be increased in patients with PAH. Increased systolic wall stress is associated with the parallel addition of sarcomeres,13 the units of contraction. An increase in diastolic volume, as with pulmonary regurgitation, is associated with the addition of sarcomeres in series and lengthening of myocytes. In PAH, an early increase in systolic wall stress is probably soon followed by an increase in diastolic wall stress. The sarcomeres show altered gene and protein expression in the remodelled myocardium and the pattern of expression reflects the type of mechanical stress. Foetal genes are re-expressed. In the failing left ventricle, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are re-expressed, whereas other genes characteristic of the adult state are down-regulated. The contractile apparatus is disturbed. Two myosin heavy-chain (MyHC) isoforms are expressed in human myocardium, {alpha}-MyHC and β-MyHC, encoded on two genes located in tandem on chromosome 14.14 {alpha}-MyHC is the fast isoform. The velocity of actin displacement is two to four times faster, the duration of force transients is shorter, and the ATPase activity is two to three times higher than for the slow isoform, β-MyHC. Therefore {alpha}-MyHC uses more ATP than β-MyHC to perform the same workload.15–17 The {alpha}-MyHC forms only 5–10% of the total myosin in the normal heart, but it is almost undetectable in the failing left ventricular myocardium and increases when myocardial function recovers.18,19 Work on transgenic rabbits suggests that switching MyHC isoforms has little functional effect on the normal heart, but that {alpha}-MyHC is protective in the stressed heart and β-MyHC is not.20 β-MyHC transgenic mice developed ventricular hypertrophy and cardiac failure with chronic infusion of isoprenaline.21 The regulatory proteins of the contractile apparatus can also change. Troponin T1 predominates in the healthy myocardium, but troponin T2, a second isoform, is increased in heart failure. Cardiac Troponin T is considered a marker of myocyte injury, and detecting this substance in the serum is indicative of a poor prognosis in patients with PAH.22 Does the stressed right ventricle undergo the same alterations in contractile proteins as the left ventricle? Are the functional implications the same?

The several stimulators of myocyte hypertrophy include noradrenaline,23 ET,24 and angiotensin,25 all of which are produced in excess in pulmonary hypertension and several of which have a role in apoptosis.

Apoptosis of cardiac myocytes is a feature of heart failure. In experimental model it occurs in response to pressure overload, mechanical stress, and a wide variety of stimuli, such as noradrenaline,26 angiotensin,27 sarcoplasmic reticulum Ca2+ overload,28 and inflammatory cytokines. Angiotensin-II stimulates apoptosis through TGF-β signalling, which acts in an autocrine manner to induce apoptosis via SMAD pathways.29 Simultaneous activation of the transcription factor activator-protein-1 (AP-1) and SMAD is required to induce apoptosis, but SMAD proteins do not appear to be necessary for AP-1-induced myocyte hypertrophy.30 Mitochondria are central to the control of apoptosis, ‘containing the necessary machinery to activate the cell-death pathway’.31 Members of the Bcl-2 gene family can increase cell death suppression by altering mitochondrial responses, and members of the proapoptotic Bcl proteins can predominate in heart failure. Therapeutic strategies designed to reduce apoptosis are being developed. In a recent study, patients in congestive heart failure were treated with metoprolol together with an angiotensin-converting enzyme (ACE) inhibitor, diuretics, and digoxin and the plasma concentrations of the apoptotic mediators, soluble Fas receptor, and Fas ligand decreased.32 These changes were associated with improvement in left ventricular function and clinical status.

Mediators of myocardial remodelling
The adrenergic system
Autonomic dysfunction is thought to be an important feature of severe pulmonary hypertension, and has been described in patients with both idiopathic PAH (IPAH) and the Eisenmenger syndrome. Two studies have reported an increase in sympathetic tone.33,34 Loss of heart rate variability is an independent risk factor for morbidity and mortality in left ventricular disease, and analysis of heart rate variability in pulmonary hypertensive patients has demonstrated early loss of circadian rhythm.34 This was caused by an increase in sympathetic tone and sympathovagal imbalance was restored by administration of Treprostinil.34 Folino et al.33 reported a reduced standard deviation of all normal-to-normal intervals (SDNN). Significant ventricular arrythmias were associated with a lower SDNN and an SDNN of <90 ms was associated with a higher right ventricular systolic pressure. Again patients with IPAH appeared to have an increase in sympathetic activity and experienced more ventricular premature beats. Vagal activity appeared greater in those with recurrent syncope.

Heart failure is generally considered an hyperadrenergic state, despite down-regulation of the β-adrenergic receptor.8 The sympathetic innervation of the heart can be demonstrated by123I-metaiodobenzlyguanidine imaging of the heart, and patients with IPAH were found to have a low heart:mediastinum activity ratio in the left ventricle.35 The ratio correlated with total PVR, right ventricular ejection fraction, and survival. Rats made pulmonary hypertensive by treatment with monocrotaline showed down-regulation of β-adrenergic receptors in both ventricles, the maximum number of binding sites decreasing by 57% in the RV and 22% in the LV at 4 weeks.36 Leineweber et al.,37 using the same experimental model, found perhaps surprisingly a reduction in plasma noradrenaline, and a reduction in RV β-adrenergic receptor density, RV neuronal noradrenaline transporter density and activity, and an increase in G-protein-coupled receptor kinase activity when the ventricle was hypertrophied. Further human and experimental works are required.

Overt right heart failure is a relatively late event in patients with pulmonary vascular disease, and accordingly, the treatment is late save for diuretic therapy. Whether early β-blockade would be beneficial is unknown. Theoretically, β-blockade could reduce the increase in L-type calcium current and cytosolic calcium transients occurring in response to β-adrenergic surges and so reduce calcium-mediated ventricular arrythmias. It might also restore ryanodine receptor function, the receptor determining the release of calcium from the sarcoplasmic reticulum in response to calcium entry via the L-channel.38 In the malfunctioning left ventricle, the failing myocardium shows defective uptake of calcium into the sarcoplasmic reticulum by the sarcoplasmic–endoplasmic reticulum uptake pump, specifically the cardiac isoform sarcoplasmic–endoplasmic reticulum uptake pump 2a. This protein and calcium transients increased in patients with end-stage congestive heart failure treated with β-blockade.39

In clinical practice, treatment with ACE inhibitors often precedes treatment with β-blockers in left heart failure, and these inhibitors have been central to the management of left ventricular failure since the mid-1980s. Studies carried out in 1985 showed that captopril improved ventricular remodelling by lessening the degree of left ventricular dilatation doing more than reduce the preload and afterload in heart failure.40 The place of these drugs in the treatment of the remodelled, failing hypertensive right ventricle remains to be determined.

Angiotensin
Angiotensin is thought to cause myocardial hypertrophy. The formation of angiotensin 1–7 from both angiotensin-I and -II is increased in the failing right ventricle of patients with IPAH, by upregulation of more than one angiotensinase.41 In addition, radioligand binding studies have demonstrated an increase in ACE-binding sites in the right ventricle of patients with IPAH and down-regulation of the angiotensin-II type-I receptor in the failing right ventricle.41 Angiotensin-II stimulation of the angiotensin-II subtype-I (AT)-I receptor upregulates mitogen- activated protein kinases that are involved in signalling cascades which promote growth and others involved in apoptosis. Angiotensin-II also stimulates collagen formation.42,43 The implications of these observations require clarification.

The ACE genotype may influence cardiac performance in pulmonary hypertension, but the evidence is not conclusive. The ACE DD genotype is associated with higher levels of ACE and greater posterior left ventricular wall thickness than in healthy people with the ID or II genotype44 and it occurs with increased frequency in patients with idiopathic and ischaemic cardiomyopathy. Abraham et al.45,46 reported an increased frequency of the DD genotype in patients with PAH, associated with a higher cardiac output than the ID or II genotype despite having similar increases in mean pulmonary arterial pressure (PAP). In contrast, Hoeper et al.47 found no association between ACE genotype, serum ACE activity, and haemodynamics in patients with IPAH. Nor have results been conclusive in patients with pulmonary hypertension associated with either chronic obstructive airways disease or high altitude.

Natriuretic peptides
Elevations in BNP levels are associated with increased mortality, and patients with a decrease in BNP levels after prostacyclin treatment survive longer than those whose levels do not improve.48 Thus, BNP is regarded as a useful biomarker of right ventricular dysfunction, but its role in the pathobiology of pulmonary hypertension is uncertain.

The cardiomyocytes secrete a family of peptide hormones, ANP and BNP. Brain natriuretic peptide production is stimulated by an increase in pressure and/or volume overload,49 resulting in an increased myocardial wall stretch.50 The hypertrophied right ventricle of monocrotaline-treated rats showed a selective 15-fold increase in BNP.51 Synthesis of BNP can also be augmented by tachycardia, glucocorticoids, thyroid hormones, and vasoactive peptides such as ET-1 and angiotensin-II, both of which are thought to play a role in the biopathology of pulmonary vascular disease52,53 BNP is synthesized and secreted by the atrial and ventricular myocardium, little is stored and rapid gene expression with de novo synthesis regulates secretion. It is synthesized as a prehormone, pro-BNP, predominantly by ventricular cardiomyocytes. It is cleaved into equal proportions of biologically active BNP, which represents the C-terminal fragment, and inactive BNP, which represents the N-terminal fragment (NT-proBNP). Both NT-proBNP and active BNP have been used as biomarkers for diagnosis and risk stratification in several cardiovascular cohorts, and their diagnostic significance is comparable. The circulating concentration of natriuretic peptides is influenced by circadian rhythm and gender. Natriuretic peptide levels are higher in women than men particularly during the reproductive years, possibly because of stimulation by female sex hormones.

The natriuretic peptides are thought to counteract to the renin-angiotensin, ET, and sympathetic nervous systems. Cardiac decompensation leads to neurohormonal activation in an attempt to maintain cardiac output and this could lead to the release of natriuretic peptides as a compensatory, adaptive response. Like ANP, BNP is a pulmonary vasodilator causing elevation in intracellular cGMP and is essential in preventing myocardial hypertrophy and fibrosis.54 Humans exposed to hypoxia had an attenuated increase in mean PAP and PVR when infused with BNP.55 The natriuretic peptides have a beneficial effect on endothelial function and the regulation of coagulation and fibrinolysis. They also inhibit platelet activation. These observations indicate the potential benefit of enhancing BNP activity, either by using natriuretic peptide analogues/recombinant BNP, or by reducing the breakdown of the endogenous product via inhibition of neutral endopeptidase or both.

Atrial and ventricular ANP secretion is stimulated by ET-1.53

Endothelin
Circulating ET levels are elevated in pulmonary hypertension and ET-1 has inotropic and mitogenic properties and causes myocyte hypertrophy. Monocrotaline-treated rats developed right ventricular hypertrophy and an increase in right ventricular ET-1.56 ET-B receptor density was increased three-fold, whereas ET-A receptors were unaffected. These responses were attenuated by a selective ET-A receptor antagonist. In another study on the monocrotaline-treated rat, the right ventricle showed a six-fold increase in ET expression, an eight-fold increase in angiotensin expression, and a 15-fold increase in BNP.51 All changes were attenuated by giving BQ-123. The left ventricle was neither hypertrophied or fibrotic, but showed upregulation of ET and angiotensin expression and abnormal contractility, a reduction in force–frequency relationships, changes which were attenuated by BQ-123. Using the same experimental model, Brunner et al.57 found that a two-fold increase in right ventricular pressure and prolongation of isovolumic contraction correlated with prolongation of intracellular Ca2+, indicating a reduced rate of sequestration.57 An ET-A receptor antagonist improved survival and normalized right ventricular pressure, diastolic relaxation, Ca2+ transport, and peak systolic and diastolic wall stress. Endothelin expression increased in the left as well as in the right ventricle of monocrotaline-treated rats, in the absence of left ventricular remodelling and the dual ET receptor antagonist bosentan normalized the depressed force–frequency relationships of this ventricle.51 A similar study on the monocrotaline-treated rat described right ventricular hypertrophy without fibrosis, and an increase in systolic contractility which compensated for the increased afterload but impaired diastolic function.58 The enhanced systolic function was in accord with an increase in levels of sarcoplasmic–endoplasmic reticulum Ca2+ ATPase (SERCA) and phosphorylated phospholamban. Endothelin-A receptor antagonism attenuated right ventricular remodelling and calcium handling, but did not influence the increase in SERC or phospholamban. Inositol-1,4,5-triphosphate receptors (IP3R) and/or diacylglycerol also appear to be involved in the inotropic effect of ET.59 The arrythmogenic effect of ET-1 was absent in the atrial myocytes of IP3R deficient mice.60

Exposure to excessive ET-1 causes myocardial hypertrophy and upregulation of the extracellular signal-related kinase ERK1/2. Exposing neonatal cardiac myocytes to ET+/–ERK1/2 inhibitor in an attempt to establish the relationship between these events demonstrated that the majority of genes potentially regulated by ET-1 are influenced by the ERK1/2 cascade.61

Analysis of the experimental data is complicated by the myocardial response to ET being species dependant and subject to experimental conditions.62 But it is evident that modulating the ET system has the potential to modify the natural history of severe pulmonary hypertension by specifically targeting the myocardium in addition to the pulmonary vasculature.

The extracellular matrix
Remodelling of the extracellular matrix includes collagen deposition and increased expression of specific metalloproteinases (MMPs) in the ventricular myocardium. In experimental right ventricular hypertrophy collagen content increases and type-III and -V collagens increase relative to type-I collagen.63,64 A compensated hypertrophy of the pressure-loaded ventricle eventually progresses to structural deterioration and heart failure. In the systemic ventricle progression from hypertrophy to dilatation is associated with a reduction in collagen cross-linking, caused by MMP activity.43,65 Myocardial expression of specific MMPs, namely gelatinase MMP-9 and stromelysin MMP-3, increases in both human and experimental dilated cardiomyopathy.66 MMPs can be induced by several molecules that are upregulated in pulmonary hypertension, including the renin–angiotensin system,43 bioactive peptides, and cytokines such as TNF-{alpha}.67 That angiotensin-II plays a central role in the remodelling process in left ventricular hypertrophy is indicated by the greater reduction in myocardial collagen seen in patients treated with the angiotensin receptor blocker, losartan, rather than the β-blocker, atenolol.68 Whether the same response would be seen in patients with right ventricular hypertrophy is unknown.

In a pacing model of left ventricular failure, MMP expression increased in association with myocardial matrix remodelling and giving an MMP inhibitor-attenuated left ventricular dilatation and improved ventricular function.66 MMP inhibitors may therefore have the potential to improve right ventricular function by regulating remodelling and in doing so would profoundly influence myocardial cell biology. The ECM is a dynamic structure composed of structural proteins, signalling molecules, and ECM–myocyte connections. Cell membrane-linked molecules include integrins, membrane-type MMPs, and ADAMs (A Disintegrin And Metalloproteinase), and these molecules are important in the regulation of cell–matrix adhesion, cell signalling, and matrix composition.69,70 It has been suggested that examining the plasma profiles of MMPs and tissue inhibitors of MMPs in the presence of left ventricular hypertrophy might act as a surrogate marker of the remodelling process.71 This might apply equally well to the remodelling right ventricle. The role of MMPs in ventricular remodelling myocyte biology makes them an intriguing therapeutic target.


   Reversible remodelling of the right ventricle
Top
 Abstract
 Introduction
 Bioenergetics of the right...
 Remodelling of the right...
 Reversible remodelling of the...
References
 
Lung transplantation is the only treatment for end-stage pulmonary vascular disease unresponsive to medical therapy. Transplantation of the lungs rather than transplantation of the heart–lung bloc is done in the expectation that the heart will remodel and recover in the presence of a normal afterload. It usually does so. The heart generally becomes significantly smaller within 3 months after transplantation. A study from the Mayo clinic showed that 3 months after orthotopic single lung transplantation in adults the volume of the right ventricular had decreased by 15% and the ejection fraction by 16%, these changes occurring in parallel with the reduction in PAP and resistance.72 A more recent echocardiographic study following bilateral lung transplantation in 17 adults with IPAH found that right ventricular size had become normal, the interventricular septum no longer deviated to the left, the high-velocity tricuspid regurgitation had disappeared and right ventricular function had improved.73 In patients with appalling right ventricular function, it can, however, be extremely difficult to be confident about predicting satisfactory recovery of right ventricular function.

Conflict of interest: Consultant to Actelion Pharmaceuticals, Encysive, GSK.


   References
Top
 Abstract
 Introduction
 Bioenergetics of the right...
 Remodelling of the right...
 Reversible remodelling of the...
 References
 

  1. Conway MA, Allis J, Ouwerkerk R, Niioka T, Rajagopalan B, Radda GK. Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic resonance spectroscopy. Lancet (1991) 338:973–976.[CrossRef][Web of Science][Medline]
  2. Conway MA, Bottomley PA, Ouwerkerk R, Radda GK, Rajagopalan B. Mitral regurgitation impaired systolic function, eccentric hypertrophy, and increased severity are linked to lower phosphocreatine/ ATP ratios in humans. Circulation (1998) 97:1716–1723.[Abstract/Free Full Text]
  3. Murray AJ, Anderson RE, Watson GC, Radda GK, Clarke K. Uncoupling proteins in human heart. Lancet (2004) 364:1786–1788.[CrossRef][Web of Science][Medline]
  4. Miall-Allen VM, Kemp GJ, Rajagopalan B, Taylor DJ, Radda GK, Haworth SG. Magnetic resonance spectroscopy in congenital heart disease. Heart (1996) 75:614–619.[Abstract/Free Full Text]
  5. Spindler M, Schmidt M, Geier O, Sandstede J, Hahn D, Ertl G, Beer M. Functional metabolic recovery of the right ventricle during Bosentan therapy in idiopathic pulmonary arterial hypertension. J Cardiovasc Magn Reson (2005) 7:853–854.[CrossRef][Web of Science][Medline]
  6. Omerovic E, Bollano E, Mobini R, Kujacic V, Madhu B, Soussi B, Fu M, Hjalmarson A, Waagstein F, Isgaard J. Growth hormone improves bioenergetics decreases catecholamines in postinfarct rat hearts. Endocrinology (2000) 141:4592–4599.[Abstract/Free Full Text]
  7. Omerovic E, Bollano E, Mobini R, Madhu B, Kujacic V, Soussi B, Hjalmarson A, Waagstein F. Selective beta(1)-blockade improves cardiac bioenergetics and function and decreases neuroendocrine activation in rats during early postinfarct remodeling. Biochem Biophys Res Commun (2001) 281:491–498.[CrossRef][Web of Science][Medline]
  8. Opie LH. Cellular basis for therapeutic choices in heart failure. Circulation (2004) 110:2559–2561.[Free Full Text]
  9. Beanlands RS, Nahmias C, Gordon E, Coates G, deKemp R, Firnau G, Fallen E. The effects of beta(1)-blockade on oxidative metabolism and the metabolic cost of ventricular work in patients with left ventricular dysfunction: a double-blind, placebo-controlled, positron-emission tomography study. Circulation (2000) 102:2070–2075.[Abstract/Free Full Text]
  10. Loffler R, Sauter R, Kolem H, Haase A, von Kienlin M. Localized spectroscopy from anatomically matched compartments improved sensitivity and localization for cardiac 31P MRS in humans. J Magn Reson (1998) 134:287–299.[CrossRef][Web of Science][Medline]
  11. Adatia I, Kemp GJ, Taylor DJ, Radda GK, Rajagopalan B, Haworth SG. Abnormalities in skeletal muscle metabolism in cyanotic patients with congenital heart disease: a 31P nuclear magnetic resonance spectroscopy study. Clin Sci (Lond) (1993) 85:105–109.[Medline]
  12. Adamopoulos S, Kemp GJ, Thompson CH, Arnolda L, Brunotte F, Stratton JR, Radda GK, Rajagopalan B, Kremastinos DT, Coats AJ. The time course of haemodynamic autonomic and skeletal muscle metabolic abnormalities following first extensive myocardial infarction in man. J Mol Cell Cardiol (1999) 31:1913–1926.[CrossRef][Web of Science][Medline]
  13. Anversa P, Ricci R, Olivetti G. Quantitative structural analysis of the myocardium during physiologic growth induced cardiac hypertrophy: a review. J Am Coll Cardiol (1986) 7:1140–1149.[Abstract]
  14. Swynghedauw B. Developmental functional adaptation of contractile proteins in cardiac: skeletal muscles. Physiol Rev (1986) 66:710–771.[Abstract/Free Full Text]
  15. Lompre AM, Schwartz K, d’Albis A, Lacombe G, Van Thiem N, Swynghedauw B. Myosin isoenzyme redistribution in chronic heart overload. Nature (1979) 282:105–107.[CrossRef][Medline]
  16. Palmiter KA, Tyska MJ, Dupuis DE, Alpert NR, Warshaw DM. Kinetic differences at the single molecule level account for the functional diversity of rabbit cardiac myosin isoforms. J Physiol (1999) 519:669–678.[Abstract/Free Full Text]
  17. Sugiura S, Kobayakawa N, Fujita H, Yamashita H, Momomura S, Chaen S, Omata M, Sugi H. Comparison of unitary displacements and forces between 2 cardiac myosin isoforms by the optical trap technique: molecular basis for cardiac adaptation. Circ Res (1998) 82:1029–1034.[Abstract/Free Full Text]
  18. Nakao K, Minobe W, Roden R, Bristow MR, Leinwand LA. Myosin heavy chain gene expression in human heart failure. J Clin Invest (1997) 100:2362–2370.[Web of Science][Medline]
  19. Miyata S, Minobe W, Bristow MR, Leinwand LA. Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ Res (2000) 86:386–390.[Abstract/Free Full Text]
  20. Marian AJ. On mice, rabbits, human heart failure. Circulation (2005) 111:2276–2279.[Free Full Text]
  21. Krenz M, Robbins J. Impact of beta-myosin heavy chain expression on cardiac function during stress. J Am Coll Cardiol (2004) 44:2390–2397.[Abstract/Free Full Text]
  22. Torbicki A, Kurzyna M, Kuca P, Fijalkowska A, Sikora J, Florczyk M, Pruszczyk P, Burakowski J, Wawrzynska L. Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension. Circulation (2003) 108:844–848.[Abstract/Free Full Text]
  23. Nootens M, Kaufmann E, Rector T, Toher C, Judd D, Francis GS, Rich S. Neurohormonal activation in patients with right ventricular failure from pulmonary hypertension: relation to hemodynamic variables and endothelin levels. J Am Coll Cardiol (1995) 26:1581–1585.[Abstract]
  24. Rubens C, Ewert R, Halank M, Wensel R, Orzechowski HD, Schultheiss HP, Hoeffken G. Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest (2001) 120:1562–1569.[CrossRef][Web of Science][Medline]
  25. Zisman LS, Keller RS, Weaver B, Lin Q, Speth R, Bristow MR, Canver CC. Increased angiotensin-(1-7)-forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme Homologue ACE2. Circulation (2003) 108:1707–1712.[Abstract/Free Full Text]
  26. Fu YC, Yin SC, Chi CS, Hwang B, Hsu SL. Norepinephrine induces apoptosis in neonatal rat endothelial cells via a ROS-dependent JNK activation pathway. Apoptosis (2006) 11:2053–2063.[CrossRef][Web of Science][Medline]
  27. Gonzalez A, Lopez B, Ravassa S, Querejeta R, Larman M, Diez J, Fortuno MA. Stimulation of cardiac apoptosis in essential hypertension: potential role of angiotensin II. Hypertension (2002) 39:75–80.[Abstract/Free Full Text]
  28. Chen X, Zhang X, Kubo H, Harris DM, Mills GD, Moyer J, Berretta R, Potts ST, Marsh JD, Houser SR. Ca2+ influx-induced sarcoplasmic reticulum Ca2+ overload causes mitochondrial-dependent apoptosis in ventricular myocytes. Circ Res (2005) 97:1009–1017.[Abstract/Free Full Text]
  29. Schroder D, Heger J, Piper HM, Euler G. Angiotensin II stimulates apoptosis via TGF-beta1 signaling in ventricular cardiomyocytes of rat. J Mol Med (2006) 84:975–983.[CrossRef][Web of Science][Medline]
  30. Schneiders D, Heger J, Best P, Michael PH, Taimor G. SMAD proteins are involved in apoptosis induction in ventricular cardiomyocytes. Cardiovasc Res (2005) 67:87–96.[Abstract/Free Full Text]
  31. Regula KM, Ens K, Kirshenbaum LA. Mitochondria-assisted cell suicide: a license to kill. J Mol Cell Cardiol (2003) 35:559–567.[CrossRef][Web of Science][Medline]
  32. Hou YP, Wu JL, Fan Q, Liu MB, Yin BL, Zhang L. Plasma concentration of Fas/Fas ligand and left ventricular function in response to metoprolol in conjunction with standard treatment. Clin Sci (Lond) (2007) 112:211–218.
  33. Folino AF, Bobbo F, Schiraldi C, Tona F, Romano S, Buja G, Bellotto F. Ventricular arrhythmias and autonomic profile in patients with primary pulmonary hypertension. Lung (2003) 181:321–328.[CrossRef][Web of Science][Medline]
  34. Rosas-Peralta M, Sandoval-Zarate J, Attie F, Pulido T, Santos E, Granados NZ, Miranda T, Escobar V. Clinical implications and prognostic significance of the study on the circadian variation of heart rate variability in patients with severe pulmonary hypertension. Gac Med Mex (2006) 142:19–28.[Medline]
  35. Sakamaki F, Satoh T, Nagaya N, Kyotani S, Oya H, Nakanishi N, Kuribayashi S, Ishida Y. Correlation between severity of pulmonary arterial hypertension and 123I-metaiodobenzylguanidine left ventricular imaging. J Nucl Med (2000) 41:1127–1133.[Abstract/Free Full Text]
  36. Ishikawa S, Honda M, Yamada S, Morioka S, Moriyama K. Biventricular down-regulation of beta-adrenergic receptors in right ventricular hypertrophy induced by monocrotaline. Jpn Circ J (1991) 55:1077–1085.[Medline]
  37. Leineweber K, Brandt K, Wludyka B, Beilfuss A, Ponicke K, Heinroth-Hoffmann I, Brodde OE. Ventricular hypertrophy plus neurohumoral activation is necessary to alter the cardiac beta-adrenoceptor system in experimental heart failure. Circ Res (2002) 91:1056–1062.[Abstract/Free Full Text]
  38. Marks AR. A guide for the perplexed: towards an understanding of the molecular basis of heart failure. Circulation (2003) 107:1456–1459.[Free Full Text]
  39. Kubo H, Margulies KB, Piacentino V III, Gaughan JP, Houser SR. Patients with end-stage congestive heart failure treated with beta-adrenergic receptor antagonists have improved ventricular myocyte calcium regulatory protein abundance. Circulation (2001) 104:1012–1018.[Abstract/Free Full Text]
  40. Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res (1985) 57:84–95.[Abstract/Free Full Text]
  41. Zisman LS, Asano K, Dutcher DL, Ferdensi A, Robertson AD, Jenkin M, Bush EW, Bohlmeyer T, Perryman MB, Bristow MR. Differential regulation of cardiac angiotensin converting enzyme binding sites and AT1 receptor density in the failing human heart. Circulation (1998) 98:1735–1741.[Abstract/Free Full Text]
  42. Hein S, Arnon E, Kostin S, Schonburg M, Elsasser A, Polyakova V, Bauer EP, Klovekorn WP, Schaper J. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation (2003) 107:984–991.[Abstract/Free Full Text]
  43. Sakata Y, Yamamoto K, Mano T, Nishikawa N, Yoshida J, Hori M, Miwa T, Masuyama T. Activation of matrix metalloproteinases precedes left ventricular remodeling in hypertensive heart failure rats: its inhibition as a primary effect of angiotensin-converting enzyme inhibitor. Circulation (2004) 109:2143–2149.[Abstract/Free Full Text]
  44. Busjahn A, Knoblauch H, Knoblauch M, Bohlender J, Menz M, Faulhaber HD, Becker A, Schuster H, Luft FC. Angiotensin-converting enzyme and angiotensinogen gene polymorphisms, plasma levels, cardiac dimensions. A twin study. Hypertension (1997) 29:165–170.[Abstract/Free Full Text]
  45. Abraham WT, Raynolds MV, Gottschall B, Badesch DB, Wynne KM, Groves BM, Lowes BD, Bristow MR, Perryman MB, Voelkel NF. Importance of angiotensin-converting enzyme in pulmonary hypertension. Cardiology (1995) 86(Suppl. 1):9–15.[CrossRef][Web of Science][Medline]
  46. Abraham WT, Raynolds MV, Badesch DB, Wynne KM, Groves BM, Roden RL, Robertson AD, Lowes BD, Zisman LS, Voelkel NF, Bristow MR, Perryman MB. Angiotensin-converting enzyme DD genotype in patients with primary pulmonary hypertension: increased frequency and association with preserved haemodynamics. J Renin Angiotensin Aldosterone Syst (2003) 4:27–30.[Abstract/Free Full Text]
  47. Hoeper MM, Tacacs A, Stellmacher U, Lichtinghagen R. Lack of association between angiotensin converting enzyme (ACE) genotype, serum ACE activity, and haemodynamics in patients with primary pulmonary hypertension. Heart (2003) 89:445–446.[Free Full Text]
  48. Nagaya N, Nishikimi T, Okano Y, Uematsu M, Satoh T, Kyotani S, Kuribayashi S, Hamada S, Kakishita M, Nakanishi N, Takamiya M, Kunieda T, Matsuo H, Kangawa K. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol (1998) 31:202–208.[Abstract/Free Full Text]
  49. King L, Wilkins MR. Natriuretic peptide receptors and the heart. Heart (2002) 87:314–315.[Free Full Text]
  50. Bruneau BG, Piazza LA, de Bold AJ. BNP gene expression is specifically modulated by stretch and ET-1 in a new model of isolated rat atria. Am J Physiol (1997) 273:H2678–H2686.[Web of Science][Medline]
  51. Lourenco AP, Roncon-Albuquerque R Jr, Bras-Silva C, Faria B, Wieland J, Henriques-Coelho T, Correia-Pinto J, Leite-Moreira AF. Myocardial dysfunction and neurohumoral activation without remodeling in left ventricle of monocrotaline-induced pulmonary hypertensive rats. Am J Physiol Heart Circ Physiol (2006) 291:H1587–H1594.[Abstract/Free Full Text]
  52. de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet (2003) 362:316–322.[CrossRef][Web of Science][Medline]
  53. Uusimaa PA, Hassinen IE, Vuolteenaho O, Ruskoaho H. Endothelin-induced atrial natriuretic peptide release from cultured neonatal cardiac myocytes: the role of extracellular calcium and protein kinase-C. Endocrinology (1992) 130:2455–2464.[Abstract/Free Full Text]
  54. Tamura N, Ogawa Y, Chusho H, Nakamura K, Nakao K, Suda M, Kasahara M, Hashimoto R, Katsuura G, Mukoyama M, Itoh H, Saito Y, Tanaka I, Otani H, Katsuki M. Cardiac fibrosis in mice lacking brain natriuretic peptide. Proc Natl Acad Sci USA (2000) 97:4239–4244.[Abstract/Free Full Text]
  55. Cargill RI, Lipworth BJ. Acute effects of ANP and BNP on hypoxic pulmonary vasoconstriction in humans. Br J Clin Pharmacol (1995) 40:585–590.[Web of Science][Medline]
  56. Jasmin JF, Cernacek P, Dupuis J. Activation of the right ventricular endothelin (ET) system in the monocrotaline model of pulmonary hypertension: response to chronic ETA receptor blockade. Clin Sci (Lond) (2003) 105:647–653.[Medline]
  57. Brunner F, Wolkart G, Haleen S. Defective intracellular calcium handling in monocrotaline-induced right ventricular hypertrophy: protective effect of long-term endothelin-A receptor blockade with 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl-)- 4-oxobut-2-enoate-sodium (PD 155080). J Pharmacol Exp Ther (2002) 300:442–449.[Abstract/Free Full Text]
  58. Stessel H, Brunner F. Effect of endothelin antagonism on contractility, intracellular calcium regulation and calcium regulatory protein expression in right ventricular hypertrophy of the rat. Basic Clin Pharmacol Toxicol (2004) 94:37–45.[Web of Science][Medline]
  59. Proven A, Roderick HL, Conway SJ, Berridge MJ, Horton JK, Capper SJ, Bootman MD. Inositol 1,4,5-trisphosphate supports the arrhythmogenic action of endothelin-1 on ventricular cardiac myocytes. J Cell Sci (2006) 119:3363–3375.[Abstract/Free Full Text]
  60. Li X, Zima AV, Sheikh F, Blatter LA, Chen J. Endothelin-1-induced arrhythmogenic Ca2+ signaling is abolished in atrial myocytes of inositol-1,4,5-trisphosphate(IP3)-receptor type 2-deficient mice. Circ Res (2005) 96:1274–1281.[Abstract/Free Full Text]
  61. Kennedy RA, Kemp TJ, Sugden PH, Clerk A. Using U0126 to dissect the role of the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade in the regulation of gene expression by endothelin-1 in cardiac myocytes. J Mol Cell Cardiol (2006) 41:236–247.[CrossRef][Web of Science][Medline]
  62. Penna C, Rastaldo R, Mancardi D, Cappello S, Pagliaro P, Westerhof N, Losano G. Effect of endothelins on the cardiovascular system. J Cardiovasc Med (Hagerstown) (2006) 7:645–652.[Medline]
  63. Morioka S, Honda M, Ishikawa S, Ishinaga Y, Yano S, Tanaka K, Moriyama K. Changes in contractile and non-contractile proteins, intracellular Ca2+ and ultrastructures during the development of right ventricular hypertrophy and failure in rats. Jpn Circ J (1992) 56:469–474.[Medline]
  64. Honda M, Yamada S, Goto Y, Ishikawa S, Yoshikane H, Ishinaga Y, Kuzuo H, Morioka S, Moriyama K. Biochemical and structural remodeling of collagen in the right ventricular hypertrophy induced by monocrotaline. Jpn Circ J (1992) 56:392–403.[Medline]
  65. Woodiwiss AJ, Tsotetsi OJ, Sprott S, Lancaster EJ, Mela T, Chung ES, Meyer TE, Norton GR. Reduction in myocardial collagen cross-linking parallels left ventricular dilatation in rat models of systolic chamber dysfunction. Circulation (2001) 103:155–160.[Abstract/Free Full Text]
  66. Spinale FG, Coker ML, Bond BR, Zellner JL. Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target. Cardiovasc Res (2000) 46:225–238.[Abstract/Free Full Text]
  67. Deschamps AM, Spinale FG. Pathways of matrix metalloproteinase induction in heart failure: bioactive molecules and transcriptional regulation. Cardiovasc Res (2006) 69:666–676.[Abstract/Free Full Text]
  68. Ciulla MM, Paliotti R, Esposito A, Diez J, Lopez B, Dahlof B, Nicholls MG, Smith RD, Gilles L, Magrini F, Zanchetti A. Different effects of antihypertensive therapies based on losartan or atenolol on ultrasound and biochemical markers of myocardial fibrosis: results of a randomized trial. Circulation (2004) 110:552–557.[Abstract/Free Full Text]
  69. Manso AM, Elsherif L, Kang SM, Ross RS. Integrins, membrane-type matrix metalloproteinases and ADAMs: potential implications for cardiac remodeling. Cardiovasc Res (2006) 69:574–584.[Abstract/Free Full Text]
  70. Deschamps AM, Spinale FG. Disruptions and detours in the myocardial matrix highway and heart failure. Curr Heart Fail Rep (2005) 2:10–17.[Medline]
  71. Deschamps AM, Spinale FG. Matrix modulation and heart failure: new concepts question old beliefs. Curr Opin Cardiol (2005) 20:211–216.[CrossRef][Web of Science][Medline]
  72. Rensing BJ, McDougall JC, Breen JF, Vigneswaran WT, McGregor CG, Rumberger JA. Right and left ventricular remodeling after orthotopic single lung transplantation for end-stage emphysema. J Heart Lung Transplant (1997) 16:926–933.[Web of Science][Medline]
  73. Kasimir MT, Seebacher G, Jaksch P, Winkler G, Schmid K, Marta GM, Simon P, Klepetko W. Reverse cardiac remodelling in patients with primary pulmonary hypertension after isolated lung transplantation. Eur J Cardiothorac Surg (2004) 26:776–781.[Abstract/Free Full Text]

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