Skip Navigation

European Journal of Heart Failure 2005 7(1):29-35; doi:10.1016/j.ejheart.2004.03.018
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Brixius, K.
Right arrow Articles by Schwinger, R. H.G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brixius, K.
Right arrow Articles by Schwinger, R. H.G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2004 European Society of Cardiology

Altered hetero- and homeometric autoregulation in the terminally failing human heart

Klara Brixiusa, Hannes Reutera, Wilhelm Blochb and Robert H.G. Schwingera,*

a Laboratory of Muscle Research and Molecular Cardiology, Department of Internal Medicine III Joseph-Stelzmann-Str. 9, 50924 Cologne (Lindenthal), Germany
b Institute of Zellular and Molecular Sport Medicine, German Sport University Cologne, Germany

* Corresponding author. Tel.: +49-221-478-3138; fax: +49-221-478-3746. E-mail address: Robert.Schwinger{at}medizin.uni-koeln.de


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective and methods: To further investigate length-dependent force generation in human heart, nonfailing (donor hearts, NF) and terminally failing (heart transplants, dilated cardiomyopathy, DCM) left ventricular myocardium was studied under various preload (4–40 mN/mm2) or length conditions. In addition, morphological studies (van Giesson Trichrome staining, electron microscopy) were performed.

Results: In NF, a biphasic increase in force of contraction (FOC) was observed after elevating the preload (4–40 mN/mm2): there was an immediate fast increase (FOCf,), followed by a slow increase over several minutes (FOCs), which was paralleled by an increase in the systolic fura-2 transient. In DCM, FOCf, FOCs and the systolic fura-2 transient were blunted and diastolic tension was increased at increasing muscle length. Only in NF, a stretched induced increase in diastolic fura-2 ratio was observed. In DCM, no obvious interstitial fibrosis and no difference in basement membrane structure and attachment were observed.

Conclusions: Since FOCf has been attributed to the Frank-Starling mechanism, whereas FOCs represents a length-dependent increase in the intracellular Ca2+-transient, the impaired length-dependent force generation in failing myocardium results from a dysregulation of both myofibrillar Ca2+-sensitivity as well as the intracellular Ca2+-homeostasis. Interstitial fibrosis may have only minor impact on force generation in human end-stage heart failure.

Key Words: Calcium • Heart failure • Contraction • Myocardium

Received September 20, 2003; Revised March 5, 2004; Accepted March 10, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
In vivo, an increase in ventricular end-diastolic volume results in an immediate increase in force of contraction (FOC) known as the Frank-Starling mechanism [1,2] or heterometric autoregulation [3] as well as in a further gradual increase in myocardial performance over the next few minutes, called Anrep effect [4] or homeometric autoregulation [3]. The initial rapid increase in force after increasing cardiac muscle length has been attributed to the properties of the cardiac myofibrils, mainly due to an increase in their sensitivity towards [Ca2+]i, whereas the slow length-/preload-dependent increase in contractility is regulated by alterations of the intracellular Ca2+-homeostasis (for review, see Refs. [5,6]). In end-stage human heart failure, the regulation of both the Ca2+-dependent myofibrillar tension [7–9] as well as the regulation of the intracellular Ca2+-homeostasis [10,11] is altered and could affect the length-/preload-dependent force generation. Therefore, we investigated preload-dependent alterations of the fast and the slow increase in contractile force in isolated, isometrically contracting left ventricular trabeculae from nonfailing and failing human myocardium as well as length-dependent alterations of the isometric force and the intracellular Ca2+-transient. Since alterations of the extracellular matrix (ECM) (e.g. interstitial fibrosis) may alter the mode of contraction, we additionally performed morphological studies in left ventricular tissue of failing and nonfailing human hearts.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1. Myocardial tissue
Human ventricular trabeculae were obtained from 16 nonfailing donor hearts that could not be transplanted for technical reasons and from 20 hearts with end-stage heart failure due to dilated cardiomyopathy at the time of heart transplantation (Table 1). The mean age of the donor group was 46±3 years (9 women, 7 men). No cardiac catheterization had been performed in the organ donor group, but none of the donors had a history of heart disease and all had normal left ventricular function as measured by echocardiography. In the heart failure group, coronary artery disease or valvular disease had been excluded by cardiac catheterization before transplantation. The investigation confirms with the principles outlined in the Declaration of Helsinki and was reviewed and approved by the local ethics committee.


View this table:
[in this window]
[in a new window]

  		Table 1 Clinical characteristics of patients with dilated cardiomyopathy

 
2.2. Preparation of the muscle strips
Muscle strips of uniform size with muscle fibers running approximately parallel to the length of the strips were dissected in aerated bathing solution (composition see below) at room temperature. For control and myopathic muscles, mean weights were 5.1±0.2 and 5.3±0.1 mg. Cross-sectional area was estimated assuming the geometry of a cylinder with a specific gravity of 1.0 and was determined from the trabeculae diameter (D) by the following formula: cross-sectional area={pi}x(D/2)2. The mean length of the preparations was 2.9±0.3 mm (n=17) for nonfailing and 3.1±0.3 mm (n=21) for failing left ventricular trabeculae. Cross-sectional area measured was 0.65±0.11 mm2 (n=17) in the nonfailing and 0.66±0.07 mm2 (n=21) in the failing preparations. Measurements were performed as described previously [7].

2.3. Measurement of force of contraction
The preparations were attached to a bipolar platinum stimulating electrode and suspended individually in 75-ml glass tissue chambers for recording of isometric contractions. The bathing solution used was a modified Tyrode's solution containing in mmol/l: NaCl 119.8, KCl 5.4, CaCl2 1.8, MgCl2 1.05, NaH2PO4 0.42, NaHCO3 22.6, Na2EDTA 0.05, ascorbic acid 0.28, glucose 5.0. It was continuously gassed with 95% O2 and 5% CO2 (T: 37 °C, pH 7.4). The preparations were electrically paced at 1 Hz.

At the end of each experiment, a force–frequency relationship (0.5–3 Hz) was measured in the preparations. Human nonfailing left ventricular trabeculae were characterized by a positive and human failing trabeculae by a negative force–frequency relation. In some nonfailing and failing preparations, the positive inotropic effect mediated by elevation of the extracellular Ca2+-concentration (15 mmol/l) was measured. There was no difference between the two groups. In addition, a test for adequate oxygenation was performed at the end of the experiments by changing the carbogen to 80% O2, 5% CO2 and 15% N2 at the preload, where force of contraction were maximal [12]. This procedure lowered oxygen tension significantly in the bathing solution and all muscle preparations in which force of contraction declined more than 10% during 30-min exposure were discarded from the evaluation (about 15% in each experimental group).

For one series of experiments, force generation was investigated increasing preload. Muscles were stretched until a defined preload-value was achieved (4–40 mN/mm2). The muscle strips were contracting under isometric conditions. For the measurement of the length-dependent contraction, muscle strips were initially pre-stretched so that active tension was developed at minimal diastolic tension (slack length). After steady-state conditions were achieved at slack length, the preparations were carefully stretched to the length at which maximum force was achieved (Lmax). Also under these conditions, the muscle strips performed isometric conditions. Experiments were performed as described previously [7].

2.4. Measurement of the intracellular Ca2+-transient
Intracellular Ca2+ was measured in isolated, electrically driven (1 Hz) left ventricular trabeculae by the fluorescence indicator fura-2 (Scientific Instruments, Heidelberg, Germany). Fura-2 ratio at Ca2+ saturation was 5.4±0.4. For data analysis, the tracings were averaged over five times under steady state conditions. Experiments were performed as described previously [13].

2.5. Histological analyses
For histological analyses, left ventricular myocardium from nonfailing and failing hearts were fixed in 4% paraformaldehyde in PBS overnight, pH 7.4, then rinsed in 0.1 M phosphate-buffered saline (PBS) for 24 h followed by storage for 12 h in PBS solution with 18% sucrose for cryoprotection and frozen at –80 °C. Cryosections were cut at 6–8 µm and stained with van Giesson Trichrome according to standard protocols. For electron microscopy of the heart tissue, the 4% paraformaldehyde immersion-fixed myocardium were post-fixed with 2% osmium tertoxide in PBS for 2 h at 4 °C. After thorough wash in PBS for three times 10 min, the tissue were block-stained with 1% uranyl acetate in 70% ethanol for 8 h. Afterwards, the specimens were dehydrated, infiltrated with and embedded in araldite, cut with a diamond knife (60 nm) on a Reichert ultramicrotome (Leica). Ultrathin sections were examined using an electron microscope (902A, Leo) after further contrasting with uranyl acetate–lead citrate.

2.6. Statistics
The data shown are mean±S.E.M. For comparison within one group, the paired t-test was applied. Otherwise, statistical significance was analyzed by the use of the Student's t-test for unpaired observations or by ANOVA; p<0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1. Preload-dependent force generation
Fig. 1A summarizes the data obtained for isometric FOC after stepwise variations of preload from 4 to 40 mN/mm2. At a preload of 4.0 mN/mm2, FOC was similar between nonfailing (6.9±1.5 mN/mm2, n=8 from 7 hearts) and failing myocardium (6.6±1.5 mN/mm2, n=8 from 7 hearts). In both nonfailing and failing left ventricular myocardium developed force increases after elevating the preload. Yet, force development was higher (P<0.05) in human left ventricular nonfailing (4 vs. 40 mN/mm2 preload: +24.2±2.9 mN/mm2, n=8 from 7 hearts) compared to failing myocardium (4 vs. 40 mN preload: +2.8±1.3 mN/mm2, n=7 from 7 hearts).


Figure 1
View larger version (20K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Preload-dependent force development measured in left ventricular papillary muscle strips of nonfailing (n=8 from 7 hearts) and failing human myocardium (n=7 from 7 hearts). Inset: schematic tracing presenting the preload-dependent alterations observed in force of contraction. After increasing preload, there was a fast increase in force of contraction (FOCf), which was followed by a slow increase (FOCs) over the next few minutes.

 
The preload-dependent total increase in FOC as given in Fig. 1A is biphasic as shown by the inlay of Fig. 1B: there is an immediate, fast increase in force (FOCf) followed by a slower increase in contractile force over several minutes (FOCs, Fig. 1B). Fig. 2 presents the preload-dependent increase in FOCf (left panel) and FOCs (right panel) from the data obtained for Fig. 1A.


Figure 2
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Fast change in force of contraction (FOCf in mN/mm2, A) as well as slow change in force of contraction (FOCs in mN/mm2, B) plotted as a function of preload (abscissa, mN/mm2) in papillary muscle strips from nonfailing ({square}) and terminally failing human myocardium ({blacksquare}). *p<0.05 vs. 4 mN/mm2 preload. #p<0.05 vs. failing.

 
The preload-dependent contractile response of FOCf was impaired (P<0.05) in failing (4 vs. 40 mN/mm2 preload: +1.8±0.3 mN/mm2) compared to nonfailing myocardium (4 vs. 40 mN/mm2 preload: +5.1±0.8, Fig. 2). FOCs was almost absent in failing myocardium (4 vs. 40 mN/mm2: –0.2±0.4 mN/mm2, Fig. 2), whereas FOCs was increased in nonfailing tissue following an increase in preload (4 vs. 40 mN/mm2: +8.7±0.8 mN/mm2). Thus, the preload-dependent impairment of total force generation in human failing myocardium may be attributed to both an impairment of the fast and the slow preload-dependent force generation.

3.2. The length-dependent force generation
To assess the length-dependence of cardiac force development, measurements were performed in isolated, electrically stimulated papillary muscle strips starting at the muscle length at which force development was optimal (Lmax) down to 80% Lmax. A length-dependent increase in force of contraction was observed for both human nonfailing (n=6 from 6 hearts) and failing (n=8 from 7 hearts) myocardium. This increase was impaired above 85% Lmax in human failing (100% Lmax, nonfailing: +15.2±2.1 mN/mm2, failing: +5.1±1.8 mN/mm2, P<0.05) and was paralleled by a diastolic dysfunction: the length-dependent increase in diastolic tension was more enhanced in failing compared to nonfailing myocardium (80% Lmax vs. Lmax, nonfailing: +8.6±4.2 mN/mm2, failing: +12.7±6.2 mN/mm2).

To investigate whether the length-dependent alterations in force of contraction were paralleled by alterations of the intracellular Ca2+-transient, the fura-2 transient was measured in isolated left ventricular muscle strips of human failing (n=5 from 4 hearts) and nonfailing (n=4 from 3 hearts) myocardium at Lmax and 80% Lmax. Fig. 3 shows original tracings of the simultaneous measurements of the intracellular Ca2+-transient (upper panel) and force of contraction (lower panel). The length-dependent increase in the systolic fura-2 ratio was more pronounced in muscle strips of nonfailing (fura-2 ratio, 80% Lmax: 1.18±0.33, Lmax: 1.83±0.45) compared to failing myocardium (fura-2 ratio, 80% Lmax: 1.04±0.22, Lmax: 1.18±0.23). In addition, a length-dependent increase in the intracellular diastolic fura-2 ratio was only observed in human nonfailing (increase in diastolic fura-2 ratio: +0.40±0.06), but not in human failing myocardium despite a profound increase in diastolic tension (Fig. 3). Although diastolic fura-2 ratio was not altered, diastolic tension increased in human failing myocardium (P<0.05).


Figure 3
View larger version (15K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Original tracings of the length-dependent alterations of the intracellular Ca2+-transient (A) and force of contraction (B) in human nonfailing and failing myocardium. The figures represent averaged tracings from five single measurements. Measurements were performed under steady state conditions. Lmax: measurement was performed at the muscle length at which maximal force development was observed. 80% Lmax: measurement was performed at 80% of the muscle length at which maximal force development was observed.

 
3.3. Morphological investigation
To investigate whether the functional differences may be due to morphological alterations of the ECM, we performed additional experiments on isolated trabeculae of left ventricular nonfailing (n=3) and failing (n=3) human myocardium. Fig. 4 demonstrates a van Giesson Trichrome staining as well as an electronic microscopic picture taken from isolated left ventricular trabeculae of human nonfailing and failing myocardium. Comparison of interstitial ECM in nonfailing (a, c) and failing (b, d) heart tissue at light microscopical (a, b) and ultrastructural level (c, d). (a, b) van Giesson staining reveals cardiomyocytes in yellow and ECM in red (arrows). No obvious interstitial fibrosis can be found in nonfailing (a) and failing myocardium (b). The transmission microscopy does not show distinct difference in basement membrane structure (arrows) and attachment between nonfailing (c) and failing (d) myocardium (M) with exception of a slight increase of adjacent stroma (AS) and density of this part of ECM. The diameter of the failing cardiomyocytes was increased.


Figure 4
View larger version (157K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Comparison of interstitial ECM in nonfailing (a, c) and failing (b, d) heart tissue at light microscopical (a, b) and ultrastructural level (c, d). (a, b) van Giesson staining reveals cardiomyocytes in yellow and ECM in red (arrows). No obvious interstitial fibrosis can be found in nonfailing (a) and failing myocardium (b). The transmission microscopy do not show distinct difference in basement membrane structure (arrows) and attachment between nonfailing (c) and failing (d) myocardium (M) with exception of a slight increase of adjacent stroma (AS) and density of this part of ECM. Bar a, b=25 µm and c, d=600 nm.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
The present study provides evidence that in the terminally failing human myocardium due to dilated cardiomyopathy both the Frank-Starling-mechanism and the Anrep effect, i.e. hetero- and homeometric autoregulation of cardiac contractility, are impaired. At subcellular levels, this may be due to both an altered Ca2+ sensitivity of the myofibrils and an altered Ca2+ supply to the myofibrils in dilated cardiomyopathy. Alterations of myocyte morphology rather than alterations of the extracellular matrix may exaggerate the impaired preload-dependent tension development in human end-stage heart failure.

4.1. Homeometric autoregulation and alterations of the intracellular Ca2+-homeostasis in human end-stage heart failure
Several sarcolemmal proteins have been shown to be involved in the stretch-induced increase in the intracellular Ca2+-transient, e.g. stretched activated Ca2+ channels [14] and the Na+/H+ exchanger and the Na+/Ca2+-exchanger [15,16] and it has been proposed that these alterations may be under neurohormonal control by angiotensin II and endothelin 1 [17]. Stretching may also modulate the sarcoplasmic reticulum Ca2+-release via Pi(3) kinase-dependent phosphorylation of AKT-kinase (protein kinase B) stimulation of the endothelial NO-synthetase [18]. Only recently, a stretch-induced increase in the intracellular cAMP-concentration has been shown in ferret papillary muscles, which has been attributed to the slow stretch response, but it was not associated with a phosphorylation of Ser16 phospholamban [19]. Thus, increasing muscle length may result in mechanisms increasing the sarcolemmal Ca2+-influx, but may not support the sarcoplasmic reticulum Ca2+-uptake. This may explain the stretch-induced increase in diastolic intracellular Ca2+, which we found in nonfailing tissue.

In human failing myocardium, the Anrep-effect was almost absent. Alterations of the intracellular Ca2+-homeostasis observed in human heart failure [11,20–22] may contribute to the decreased homeometric autoregulation. Nevertheless, the length-dependent increase in diastolic tension was much more pronounced in human failing than in human nonfailing myocardium. These results indicate that factors beyond the dysregulation of the intracellular Ca2+-homeostasis may contribute to the diastolic dysfunction observed in human heart failure.

4.2. Heterometric autoregulation and myofibrillar in end-stage human heart failure
The initial rapid increase in force after increasing cardiac muscle length has been attributed to the properties of the cardiac myofibrils, mainly due to an increase in their sensitivity to [Ca2+]i (for review, see Ref. [5]). The present study provides evidence that the length-dependent regulation of myofibrillar tension is altered in human end stage heart failure. In line with this, it has been shown that myofibrillar Ca2+-sensitivity is increased in human left ventricular failing myocardium and that the length-dependent increase in myofibrillar Ca2+-sensitivity is missing, which has been attributed in part to a reduced cAMP-dependent phosphorylation of cardiac troponin I [7–9]. Beside alterations in the phosphorylation status, mutations or alterations in the isoform expression of the contractile proteins may influence myofibrillar tension development (e.g. TNT [23]).

It has been suggested that physical factors arising from the interaction of intra- and extracellular structures may also influence the preload-/length-dependent force generation [5]. From the tissue used in our study, we conclude that an increase in fibrotic tissue may have only minor impact on the length-dependent force development in human failing myocardium. In line with this, no differences were found in the fibrous tissue component between myocardium of patients suffering from dilated cardiomyopathy and control patients [24,25]. However, from these studies, we cannot exclude that isoform alterations take place in dilative cardiomyopathy, which may influence cardiac force development.

Evidence is provided from the present and from former studies that the alterations of the length-/preload-dependent tension development may be mainly a cellular phenomenon. Morphological electronic microscopic studies in left ventricular tissue of heart failure patients in NYHA IV have provided evidence that cardiomyocytes of patients suffering from dilated cardiomyopathy were up to three- to four-times wider and longer as compared to cells of nonfailing hearts [26]. However, at the same time, myofibrils lack in many cellular areas, in the center and the periphery of the cells [26]. Furthermore, atrophic cells were observed that contained only remnants of myofilaments [26]. Thus, although myocyte hypertrophy may compensate for the depressed cardiac function in early states of heart failure (e.g. during the development of cardiac hypertrophy), a myofibrillar disorganization may occur in the long-term progression of the disease, which disables the heart to react adequately in situations of increased cardiac load as can be seen from the present experiments. In this context, it has been suggested that many myocardial cells, which lack myofilaments but contain an abnormal amount of cytoskeletal elements, will probably survive but certainly do not contribute to the contractile function. However, direct functional evidence for this has to be given in future studies.

It has been reported that not all tissue blocks show these cellular morphological alterations [26]. This focal localization of structural changes [26] in diseased myocardium may explain part of the variations in the results obtained for the length-/preload-dependent measurements in human myocardium [7,27–29].

4.3. Limitation of the study
The experiments of the present study are in vitro experiments performed under isometric conditions. Under these circumstances, force development may be smaller than that observed under in vivo conditions. Furthermore, we cannot exclude an influence of dopamine infusion prior to harvesting hearts in controls on the phosphorylation status of proteins involved in the regulation of excitation–contraction coupling.


   Acknowledgements
 
We are indebted to all colleagues of the Department of the Cardiothoracic Surgery at the University of Cologne (Director: Prof. Dr. R.E. de Vivie) and Munich (Director: Prof. Dr. B. Reichart) for providing us with human myocardial samples. Experimental work was supported by the Deutsche Forschungsgemeinschaft (DFG to R.H.G.S.) and Köln Fortune (to K.B. and R.H.G.S.).


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

  1. Frank O. Zur Dynamik des Herzmuskels. Z. Biol. (1895) 32:370–437.
  2. Starling E.H. Linacre lecture on the law of the heart: 1915. (1918) London, England: Longmans.
  3. Sarnoff S.J., Mitchell J.H., Gilmore J.P., Remensnyder J.P. Homeometric autoregulation in the heart. Circ. Res. (1960) 8:1077–1091.[Abstract/Free Full Text]
  4. Von Anrep G. On the part played by the suprarenals in the normal vascular reaction of the body. J. Physiol. (1912) 45:307–317.[Free Full Text]
  5. Allen D.G., Kentish J.C. The cellular basis of the length-tension relation in cardiac muscle. J. Mol. Cell. Cardiol. (1985) 17:821–840.[Web of Science][Medline]
  6. Calaghan S.C., White E. The role of calcium in the response of cardiac muscle to stretch. Prog. Biophys. Mol. Biol. (1999) 71:59–90.[CrossRef][Web of Science][Medline]
  7. Schwinger R.H.G., Bohm M., Koch A., et al. The failing human heart is unable to use the Frank-Starling mechanism. Circ. Res. (1994) 74:959–969.[Abstract/Free Full Text]
  8. Wolff M.R., Buck S.H., Stoker S.W., Greaser M.L., Mentzer R.M. Myofibrillar calcium sensitivity of isometric tension is increased in human dilated cardiomyopathies: role of altered beta-adrenergically mediated protein phosphorylation. J. Clin. Invest. (1996) 98:167–176.[Web of Science][Medline]
  9. van der Velden J., de Jong J.W., Owen V.J., Burton P.B., Stienen G.J. Effect of protein kinase A on calcium sensitivity of force and its sarcomere length dependence in human cardiomyocytes. Cardiovasc. Res. (2000) 46:487–495.[Abstract/Free Full Text]
  10. Beuckelmann D.J., Nabauer M., Erdmann E. Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation (1992) 85:1046–1055.[Abstract/Free Full Text]
  11. Schwinger R.H.G., Bohm M., Schmidt U., et al. Unchanged protein levels of SERCA II and phospholamban but reduced Ca2+ uptake and Ca2+-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts. Circulation (1995) 92:3220–3228.[Abstract/Free Full Text]
  12. Paradise N.F., Schmitter J.L., Surmitis J.M. Criteria for adequate oxygenation of isometric kitten papillary muscle. Am. J. Physiol. (1981) 241:H348–H353.[Web of Science][Medline]
  13. Brixius K., Pietsch M., Hoischen S., et al. Effect of inotropic interventions on contraction and Ca2+ transients in the human heart. J. Appl. Physiol. (1997) 83:652–660.[Abstract/Free Full Text]
  14. Guharay F., Sachs F. Stretch-activated single ion channel currents in tissue-cultured embryonic chick skeletal muscle. J. Physiol. (1984) 352:685–701.[Abstract/Free Full Text]
  15. Alvarez B.V., Perez N.G., Ennis I.L., et al. Mechanisms underlying the increase in force and Ca2+ transient that follow stretch of cardiac muscle: a possible explanation of the Anrep effect. Circ. Res. (1999) 85:716–722.[Abstract/Free Full Text]
  16. Perez N.G., de Hurtado M.C., Cingolani H.E. Reverse mode of the Na+–Ca2+ exchange after myocardial stretch: underlying mechanism of the slow force response. Circ. Res. (2001) 88:376–382.[Abstract/Free Full Text]
  17. Calaghan S.C., White E. Contribution of angiotensin II, endothelin I and the endothelium to the slow inotropic response to stretch in ferret papillary muscle. Pflugers Arch. (2001) 441:514–520.[CrossRef][Web of Science][Medline]
  18. Petroff M.G., Kim S.H., Pepe S., et al. Endogeneous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes. Nat. Cell Biol. (2001) 3:867–873.[CrossRef][Web of Science][Medline]
  19. Calaghan S.C., Coyler J., White E. Cyclic AMP but not phosphorylation of phospholamban contributes to the slow inotropic response to stretch in ferret papillary muscle. Pflugers Arch. (1999) 437:780–782.[CrossRef][Web of Science][Medline]
  20. Hasenfuss G., Reinecke H., Studer R., et al. Relation between myocardial function and expression of sarcoplasmic reticulum Ca2+-ATPase in failing and nonfailing human myocardium. Circ. Res. (1994) 75:434–442.[Abstract/Free Full Text]
  21. Piot C., Lemaire S., Albat B., Seguin J., Nargeot J., Richard S. High frequency-induced upregulation of human cardiac calcium currents. Circulation (1996) 93:120–128.[Abstract/Free Full Text]
  22. Hasenfuss G., Schillinger W., Lehnart S.E., et al. Relationship between Na+–Ca2+-exchanger protein levels and diastolic function of failing human myocardium. Circulation (1999) 99:641–648.[Abstract/Free Full Text]
  23. Anderson P.A., Malouf N.N., Oakeley A.E., Pagani E.D., Allen P.D. Troponin T isoform expression in humans. A comparison among normal and failing adult heart, fetal heart, and adult and fetal skeletal muscle. Circ. Res. (1991) 69:1226–1233.[Abstract/Free Full Text]
  24. Rose A.G., Beck W. Dilated (congestive) cardiomyopathy: a syndrome of severe cardiac dysfunction with remarkably few morphological features of myocardial damage. Histopathology (1985) 9:367–379.[CrossRef][Web of Science][Medline]
  25. de Leeuw N., Ruiter D.J., Balk A.H., de Jonge N., Melchers W.J., Galama J.M. Histopathologic findings in explanted heart tissue from patients with end-stage idiopathic dilated cardiomyopathy. Transpl. Int. (2001) 14:299–306.[Web of Science][Medline]
  26. Schaper J., Froede R., Hein S., Buck A., Hashizume H., Speiser B., et al. Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation (1991) 83:504–514.[Abstract/Free Full Text]
  27. Vahl C.F., Timek T., Bonz A., Fuchs H., Dillman R., Hagl S. Length dependence of calcium- and force-transients in normal and failing human myocardium. J. Mol. Cell. Cardiol. (1998) 30:957–966.[CrossRef][Web of Science][Medline]
  28. Holubarsch C., Ruf T., Goldstein D.J., et al. Existence of the Frank-Starling mechanism in the failing human heart. Investigations on the organ, tissue, and sarcomere levels. Circulation (1996) 94:683–689.[Abstract/Free Full Text]
  29. Kayhan N., Bodem J., Vahl C., Hagl S. The positive staircase (force–frequency relationship) and the Frank-Starling merchanism are altered in atrial myocardium of patients in end-stage heart failure transplanted for dilative cardiomyopathy. Transplant. Proc. (2002) 34:2185.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J Am Coll CardiolHome page
V. Soukoulis, J. B. Dihu, M. Sole, S. D. Anker, J. Cleland, G. C. Fonarow, M. Metra, E. Pasini, T. Strzelczyk, H. Taegtmeyer, et al.
Micronutrient deficiencies an unmet need in heart failure.
J. Am. Coll. Cardiol., October 27, 2009; 54(18): 1660 - 1673.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Brixius, K.
Right arrow Articles by Schwinger, R. H.G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brixius, K.
Right arrow Articles by Schwinger, R. H.G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?