© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Left ventricular assist device support reverses altered cardiac expression and function of natriuretic peptides and receptors in end-stage heart failure
aInstitute of Pharmacology and Toxicology and Interdisciplinary Center for Clinical Research, Universitätsklinikum Münster, Domagkstrasse 12, D-48129 Münster, Germany
bDepartment of Cardiology and Angiology, Universitätsklinikum Münster, Germany
cDepartment of Thoracic and Cardiovascular Surgery, Universitätsklinikum Münster, Germany
dInstitute of Pathology, Universitätsklinikum der Universität Duisburg-Essen, Germany
* Corresponding author. Tel.: +49 251 83 52597; fax: +49 251 83 55501. Email address: mkuhn{at}uni-muenster.de
Received 5 May 2004; revised 23 June 2004; accepted 1 July 2004
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. Discussion5. LimitationsReferences |
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Objective: Atrial (ANP) and B-type natriuretics peptides (BNP) via their guanylyl cyclase-A (GC-A) receptor not only regulate arterial blood pressure and volume but also exert local antihypertrophic, antifibrotic and lusitropic effects in the heart. To elucidate whether cardiac hypertrophy/insufficiency and reversal is associated with changes in the local responsiveness to NPs, we compared the mRNA expression of ANP, BNP and receptors and the responsiveness of GC-A to ANP in left ventricular tissue obtained from 10 patients with congestive heart failure (CHF) before and after hemodynamic unloading by left ventricular assist device (LVAD) support.
Methods and results: Quantitative "real time" RT-PCR demonstrated that the mRNA expression levels of ANP, BNP and the NP-metabolizing NPR-C receptor were both markedly increased in human failing hearts. GC-A mRNA expression levels were not different from nonfailing hearts, but cGMP production by GC-A in response to ANP was nearly abolished. Reversal of cardiomyocyte hypertrophy during LVAD support was accompanied by normalization of ANP, BNP and NPR-C mRNA levels and a significant recovery of GC-A responsiveness to ANP.
Conclusion: In CHF patients, increased local clearance by NPR-C receptors and diminished responsiveness of cardiac GC-A might impair the local antihypertrophic effects of natriuretic peptides and contribute to the progression of cardiac hypertrophy and insufficiency. Reverse remodeling during LVAD support reverses these changes and can thereby recuperate the local protective effects of ANP and BNP.
KEYWORDS Natriuretic peptide; Heart failure; Transplantation
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. LimitationsReferences |
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Cardiac atrial (ANP) and B-type natriuretic peptides (BNP) not only act as circulating endocrine factors to maintain arterial blood pressure and volume homeostasis but also as local auto/paracrine antihypertrophic (ANP) and antifibrotic (BNP) cardiac factors [1]. Thus, targeted overexpression of the ANP/BNP receptor guanylyl cyclase-A (GC-A) in cardiomyocytes exerts antihypertrophic effects in vivo [2]. Conversely, mice with conditional, selective deletion of GC-A in cardiomyocytes have normal arterial blood pressure levels, and despite this, significant cardiac hypertrophy and impaired diastolic relaxation [3]. Notably, BNP-deficient mice do not have hypertension or cardiac hypertrophy but are susceptible to cardiac fibrosis [4]. Taken together, these observations in monogenetic mouse models indicate that NP/GC-A/cGMP signaling not only protects the heart from pressure and volume overload, but also provides a local cell-growth moderating and possibly lusitropic circuit within the heart itself. In particular, this system can counteract Angiotensin-II-mediated excessive remodeling [5].
Patients with cardiac hypertrophy and/or congestive heart failure (CHF) have elevated cardiac and plasma levels of ANP and BNP, with these peptide levels being highly related to the severity of the disease. However, diuresis/natriuresis, vasodilatation as well as vascular cGMP synthesis in response to exogenous ANP or BNP are markedly attenuated, indicating a down-regulation or impaired receptor or postreceptor responsiveness of GC-A in peripheral tissues of CHF patients [6–8]. Increased peripheral expression of NPR-C receptors, mediating enhanced metabolic clearance of NPs, may also be involved [9,10]. It is not known whether attenuation of the endocrine ANP effects in CHF patients is accompanied by local cardiac alterations of NP/GC-A/cGMP signaling. This is important because our recent studies in mice with cardiomyocyte-restricted deletion of GC-A indicate that an inhibition of the local cardiac ANP effects facilitates or can even initiate cardiac hypertrophy and diastolic dysfunction [3]. Using "real-time" quantitative RT-PCR and stimulation of cGMP production, in the present study, we determined the level of transcripts of both the biologically active GC-A and the NP-metabolizing NPR-C receptors as well as ANP-stimulated GC-A activity in left ventricular tissue obtained from patients with CHF before and after long-term hemodynamic unloading. Investigation of paired heart tissue obtained immediately after left ventricular assist device (LVAD) implantation and later during cardiac transplantation provides the unique opportunity to study the effects of volume/pressure unloading within the same patient. Compared with "nonfailing" hearts, the cardiac GC-A/NPR-C ratios and ANP-stimulated GC-A activity were markedly decreased in both ischemic heart disease and dilated cardiomyopathy. Partial reversal of cardiac hypertrophy during LVAD support was accompanied by normalization of cardiac ANP/BNP expression and GC-A/NPR-C ratios and a significant recovery of GC-A responsiveness to ANP. We conclude that chronic hemodynamic unloading by LVAD reverses altered cardiac gene expression and function of NP and their receptors in end-stage heart failure and thereby might reintegrate at least in part their local protective actions.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. LimitationsReferences |
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2.1 Patient material
Paired transmural myocardial tissue from 10 patients with terminal heart failure (five with dilated cardiomyopathy and five with ischemic heart disease) was sampled from the left ventricular apex at the time of LVAD implantation (pre-LVAD) and removal before transplantation (post-LVAD) (Table 1). The mean duration of LVAD support was 210 days (range 110–295 days). The material used in the study is routinely removed during surgery (both during LVAD implantation and at the time of heart transplantation). Only tissue assessed as viable by macroscopic examination was taken to avoid sampling of scar tissue. Control tissue was taken from the left ventricle of unused donor hearts (n=8 "nonfailings"). One part of the samples was snap frozen in liquid nitrogen and processed for mRNA and GC-A activity determinations. The other part was fixed in 4% formalin for morphometrical analyses. The investigation conforms to the principles outlined in the Declaration of Helsinki and was approved by the local ethics committee.
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2.2 Morphometrical analysis
Periodic acid Schiff (PAS)-stained slides were used to determine cardiomyocyte diameter. By evaluating 100 cells per specimen on the nuclear level with the assist of an analysis system (KS 300, Zeiss), we calculated the mean cardiomyocyte diameter as previously described [11]. The interstitial collagen fraction was determined on Sirius-red-stained slides. Twenty visual fields at a final magnification of 200 were analyzed under the polarizing microscope and the total birefractive collagen was detected. Interstitial collagen fractions were calculated as ratios between the collagen area and the total ventricular area in the corresponding section, in percent [11]. Areas with perivascular fibrosis and replacement fibrosis were excluded from the measurement.
2.3 Quantitation of cardiac mRNA expression of natriuretic peptides and receptors by real-time RT-PCR
A quantitative analysis of ANP, BNP, GC-A and NPR-C mRNA expression was performed using the LightCycler Detection System (Roche Diagnostics) [12]. The following oligonucleotide primers and fluorogenic probes were used (Tib Molbiol, Berlin): for ANP, sense primer 5'-TTCTCCACCACCACCGTGA; antisense primer 5'-GGCTCCAATCCTGTCCATCC (resulting in a 411-bp amplicon); detection probe 5'-LC-Red 640-CCAACGCAGACCTGATGGATTTCA; anchor probe 5'-AGCTAATCCCATGTACAATGCCGTG; for BNP, sense primer 5'-CTTGGAAACGTCCGGGTTA; antisense primer 5'-TAATGCCGCCTCAGCACTT (294-bp amplicon); detection probe 5'-LC-Red 640-CCTGCAGCTCCGACAGTTTGCC; anchor probe 5'-GGGCTCCAGGGATGTCTGCTCC; for GC-A, sense primer 5'-CCAGTTCCAAGTCTTTGCCAAG; antisense primer 5'-AAACAGCATGCCCTTGACGA (304 bp amplicon); detection probe 5'-LC-Red 640-CCACGAGGTTGCCCTTATAATATGCT; anchor probe 5'-GCGTTTACGGTTTCACACGTTTCAC; for NPR-C, sense primer 5'-TCTGGAAGACATCGTGCGCAA; antisense primer 5'-ATCGTGGAATCCTTCAACAAACA (542 bp amplicon); detection probe 5'-LC-Red 640-CACTGCTCGCACACATGATCACCAC; anchor probe 5'-ACCAGCATGATGCTCCGGATGGT. Quantitative PCR analysis was performed using the Light-Cycler software (Roche Diagnostics). Data were calculated from the kinetic curve of the PCR by interpolation with a standard curve generated by using known amounts of the target DNA [13]. All transcripts were normalized to β2-microglobulin [14].
2.4 Guanylyl cyclase assay
ANP-dependent guanylyl cyclase activity in membranes prepared from left ventricular homogenates was determined as described [3]. To initiate cyclase activity, 50 µg membrane protein was incubated in assay buffer [25 mM HEPES, 4 mM MgCl2, 1 mM 3-isobutyl-1-methylxanthine, 2 mM ATP, 2 mM GTP, 30 mM phosphocreatine, 400 µg/ml creatine phosphokinase (185 units/mg) and 0.5 mg/ml BSA] at 37 °C, with or without ANP. At 10 min of incubation, the reaction was stopped by addition of ice-cold 100% (v/v) ethanol (final concentration 70%). After centrifugation (3000xg, 5 min, 4 °C), the supernatants were dried in a speed vacuum concentrator, resuspended in sodium acetate buffer (50 mM, pH 6.0) and acetylated, and the cGMP content was determined by radioimmunoassay [3]. cGMP production was normalized to protein content (50 µg/sample) and the increase in cGMP content in ANP-treated as compared to parallel vehicle-treated membrane preparations of the same heart was calculated.
2.5 Statistical analysis
Data before and after LVAD support from the same patient were tested for significance with the Wilcoxon matched-pair test. Correlations between ANP or BNP and NPR-C as well as between the different target genes and cardiomyocyte diameters were calculated using linear regression analysis. Comparison with the NF control tissues was done by unpaired Student's t-test. Data are presented as the means±SEM.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. LimitationsReferences |
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3.1 Patients under LVAD support
The mean left ventricular end-diastolic diameter (LVEDD) decreased significantly from 70.1±9.8 mm before LVAD implantation to 62.8±13.4 mm at the end of LVAD support (P
0.05) as estimated by echocardiography, and, accordingly, mitral insufficiency score decreased simultaneously but reached nonsignificance (P=0.59). The main difference in medication between pre- and post-LVAD was the increase in β-receptor blocker recipients (seven patients before, all patients after LVAD) and the reduction of catecholamines (five patients before, one patient after LVAD) (Table 1). Morphometrical analyses of PAS-stained tissue sections demonstrated a significant decrease in cardiomyocyte diameters during LVAD support (pre-LVAD 23.2±2.6 µm, post-LVAD 19.9±2.1 µm; P<0.05). However, cardiomyocytes of CHF patients remained significantly enlarged as compared to nonfailing controls (14.04±2.4 µm) (Table 1). Sirius red stainings revealed increased interstitial collagen fractions that did not change after LVAD support (pre-LVAD 2.7±1.4%, post-LVAD 2.7±0.9%) (Table 1).
3.2 Reversible increases in the expression of ANP, BNP and NPR-C in end-stage heart failure
Quantitative RT-PCR analysis demonstrated that left ventricular mRNA expression levels of ANP (by 39-fold), BNP (by 27-fold) and of the NP-clearing NPR-C receptor (by 4.1-fold) were markedly increased in left ventricular biopsies from CHF patients as compared to nonfailing controls (Fig. 1, pre-LVAD). During chronic hemodynamic unloading, the mRNA levels of ANP and NPR-C markedly decreased almost to the levels in control hearts (Fig. 1, post-LVAD). Similarly, BNP mRNA levels significantly decreased during LVAD support (not shown). When all samples were analyzed together, there was a significant positive correlation between ANP or BNP and NPR-C mRNA expression levels (r=0.546, P=0.013 for ANP; R=0.76, P=0.0001 for BNP) as well as between the mRNA levels of ANP, BNP, NPR-C and cardiomyocyte size (see Fig. 2). In contrast to NPR-C expression, cardiac GC-A mRNA levels in CHF were not different to "nonfailing" controls and were not affected by LVAD support (Fig. 1). However, subsequent to the reversible changes in NPR-C expression, the ratios of GC-A receptor to NPR-C were decreased in failing hearts and significantly increased by 
2.9-fold after LVAD support (Fig. 1). When plotting the ratios of GC-A/NPR-C expression vs. cardiomyocyte diameters, there was an obvious reciprocal trend, but no significant inverse correlation (P=0.054; see Fig. 2).
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P<0.05 vs. NF; *P<0.05 vs. pre-LVAD).
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3.3 Reversible decreases of cardiac GC-A responsiveness to ANP in end-stage heart failure
To further characterize the local activity of the ANP/GC-A system, membrane-bound guanylyl cyclase activity was assayed in left ventricular biopsies from nonfailing control hearts as well as CHF patients before and after LVAD support. ANP-stimulated (10 nM–1 µM) cGMP synthesis in CHF samples was nearly abolished (Fig. 3, pre-LVAD). Reverse remodeling during LVAD support led to a significant increase in ANP-dependent cardiac GC-A activity (Fig. 3). In fact, GC-A responsiveness in "post-LVAD" ventricles was similar to nonfailing controls.
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. LimitationsReferences |
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Our study shows that increased cardiac ventricular ANP and BNP expression in CHF patients is accompanied by increased cardiac expression of the NP-metabolizing NPR-C receptor, decreased ratios of GC-A to NPR-C receptors, and abolished cGMP-responsiveness of GC-A to ANP. Reverse remodeling of the heart during chronic hemodynamic unloading by LVAD reverses these changes and reintegrates the local responsiveness of GC-A to ANP. Our recent observations in mice with cardiomyocyte-restricted deletion of GC-A [3] suggest that recuperation of the protective cardiac effects of ANP and BNP might contribute to the partial reversal of cardiac hypertrophy observed in CHF patients during LVAD support.
Several studies have shown that GC-A mRNA and receptor number are reduced in cultured cells stimulated for a prolonged period of time with high ANP concentrations [15]. In fact, functional analysis of the GC-A gene promoter revealed a putative cGMP-responsive element, suggesting that the ANP-dependent down-regulation of GC-A mRNA is cGMP dependent [16,17]. However, other studies could not reproduce this result [18]. In accordance with the latter, in the present study, cardiac GC-A mRNA expression levels were not affected by the marked increases (pre-LVAD) and decreases (post-LVAD) in ANP and BNP levels. Thus, it is possible that different types of tissues and cells rely on different mechanisms to regulate GC-A expression. In addition, the referred studies [16,17] were performed in tissue culture and cells of nonhuman origin and the processes modulating GC-A expression under these in vitro conditions may differ markedly from the processes regulating GC-A expression in the human myocardium in vivo.
In line with our study, published reports have already suggested that attenuation of the endocrine vasodilating and diuretic/natriuretic responses of CHF patients to ANP and BNP is partly due to an up-regulation of NPR-C receptors, leading to increased sequestration and degradation of these peptides [9,10]. Even more, in our study, cardiac ANP/BNP and NPR-C expression levels were positively correlated. Increased NPR-C expression probably contributes to but not fully explains the blunted cGMP response of systemic [8] and cardiac GC-A to NPs. Biochemical modifications of GC-A such as dephosphorylation in the presence of high ANP/BNP concentrations (homologous desensitization) or of growth factors such as Angiotensin II and endothelin (heterologous desensitization) might also be involved (comprehensively reviewed in Ref. [19]). Although these processes so far have only been demonstrated in vitro, they may also interfere with NP/GC-A signaling under certain pathological conditions in vivo, particularly in diseased hearts. Ultimately, which of these processes (increased NPR-C expression, posttranslational modifications of GC-A) account for the diminished responsiveness of cardiac GC-A in CHF patients remains an open and important question for our future studies.
Morphometrical analyses in comparison with nonfailing control hearts showed that hemodynamic unloading significantly but not fully reversed cardiac hypertrophy in CHF patients. Notably, overall, there was a clear positive correlation between cardiomyocyte diameters and cardiac ANP, BNP as well as NPR-C mRNA expression levels. However, whereas cardiac hypertrophy did not fully reverse during LVAD support, the changes of ANP, BNP and receptors were completely reversible (i.e., cardiac NP and NPR-C expression levels as well as GC-A activity "post-LVAD" were not significantly different from nonfailing controls), suggesting that they are partly independent from cardiac hypertrophy but also dependent from other local variables such as myocyte stretch. In addition, patient medication might also have a role. For instance, β-adrenoceptor antagonists are known to augment plasma ANP, BNP and cGMP concentrations despite their hypotensive actions [20]. However, in our study, group β-blocker therapy was intensified during LVAD support and despite this, ANP and BNP expression levels markedly decreased. It was also reported that β-blockers can decrease NPR-C expression levels and thereby increase cGMP-responsiveness to ANP [21]. Thus, the increase in β-blocker medication and the reduction of catecholamines (see Table 1) might contribute to diminished NPR-C expression and recuperation of GC-A/cGMP responsiveness after LVAD support.
Intriguingly, the regression of cardiac hypertrophy during LVAD support was not accompanied by a significant reduction of total interstitial collagen content, as quantified on Sirius-red-stained tissue slides. These results are consistent with a previous report by Li et al. [22], which, by a biochemical method, also demonstrated that total cardiac collagen content does not change after LVAD support, the duration of support being similar to our study. However, by biochemical analyses, these authors demonstrated that the ratio of insoluble (undenatured) to total collagen increases during hemodynamic unloading, together with a down-regulation of matrix metalloproteinases (MMP) [22]. Thus, reduced MMP activity may lead to diminished damage to the matrix collagen, and, together with the regression of cardiomyocyte hypertrophy observed in the present as well as other published studies [23], contribute to the functional recovery and LV plasticity after LVAD support.
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5. Limitations |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. LimitationsReferences |
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Because of the low patient number, this study is not able to differentiate between dilated cardiomyopathy and ischemic heart disease. Another important limitation is the lack of specific antibodies for immunohistochemical studies, which hindered us to distinguish which of the various cell types within the heart account for the changes in NPR-C expression levels. Third, this study could not address the functional implications of the increased cardiac NPR-C expression levels in CHF patients, i.e., whether these changes in receptor expression were accompanied by increased local internalization and degradation of ANP and BNP. Last, our study could not identify the posttranslational modifications of cardiac GC-A possibly contributing to the diminished responsiveness to ANP in CHF. The development of phosphospecific antibodies to characterize GC-A dephosphorylation/desensitization [19] in vivo will be a main goal for our future studies.
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Acknowledgements |
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This work was supported by the deutsche Forschungsgemeinschaft (DFG KU 1037/4-1), the University of Münster (Interdisziplinäre Klinische Forschung Ku 1/040/04) and by the IFORES (to H.A.B.).
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Notes |
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Time for primary review 21 days
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References |
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