Biomedical subjects

B Pieske

Publications and source records attributed to B Pieske.

At least 37 records · Page 2Linked to original sources

PubMed1999

Haemodynamic effects of intracoronary pyruvate in patients with congestive heart failure: an open study.

BACKGROUND: Pyruvate, as an intermediate in the Krebs cycle, is an important source of energy for myocardium and improves contractility of normal, hypoxic, and postischaemic animal myocardium. We investigated the effect of intracoronary pyruvate in patients with congestive heart failure. METHODS: Haemodynamic measurements were done in eight patients with dilated cardiomyopathy after two 15 min infusions of pyruvate into the left main coronary artery and after saline washout of pyruvate. FINDINGS: There were no significant differences between the two pyruvate concentrations. Application of pyruvate resulted in a 23% increase in cardiac index (p<0.05), a 38% increase in stroke-volume index (p<0.05), and a 36% decrease in pulmonary capillary wedge pressure (p<0.05). Heart rate decreased significantly by 11%. Mean aortic pressure and systemic vascular resistance did not change. Most of the effects of pyruvate were reversed 15 min after the infusion stopped. INTERPRETATION: Pyruvate has the profile of a favourable inotropic substance. Other modes of administration need to be studied.

Cardiac Catheterization↗

PubMed1999

Functional effects of endothelin and regulation of endothelin receptors in isolated human nonfailing and failing myocardium.

BACKGROUND: An activated endothelin (ET) system may be of pathophysiological relevance in human heart failure. We characterized the functional effects of ET-1, ET receptors, and ET-1 peptide concentration in left ventricular myocardium from 10 nonfailing hearts (NF) and 27 hearts in end-stage failure due to idiopathic dilative cardiomyopathy (DCM). METHODS AND RESULTS: Inotropic effects were characterized in isolated muscle strips (1 Hz; 37 degrees C). ET-1 0.0001 to 0.3 micromol/L significantly (P<0.05) increased twitch force by maximally 59+/-10% in NF and by 36+/-11% in DCM (P<0.05 versus NF). Preincubation with propranolol 1 micromol/L and prazosin 0.1 micromol/L did not affect the response to ET-1, but the mixed ET receptor antagonist bosentan and the ETA receptor antagonist BQ-123 shifted the concentration-response curves for ET-1 rightward. The ETB receptor agonist sarafotoxin S6c 0.001 to 0.3 micromol/L had no functional effects. The inotropic response to ET-1 was not associated with increased intracellular Ca2+ transients, as assessed in aequorin-loaded muscle strips. ET receptor density (Bmax; radioligand binding) was 62.5+/-12.5 fmol/mg protein in NF and 122. 4+/-24.3 fmol/mg protein in DCM (P<0.05 versus NF). The increase in Bmax in DCM resulted from an increase in ETA receptors without change in ETB receptors. ET-1 peptide concentration (radioimmunoassay) was higher in DCM than in NF (14 447+/-2232 versus 4541+/-1340 pg/mg protein, P<0.05). CONCLUSIONS: ET-1 exerts inotropic effects in human myocardium through ETA receptor-mediated increases in myofibrillar Ca2+ responsiveness. In DCM, functional effects of ET-1 are attenuated, but ETA receptor density and ET-1 peptide concentration are increased, indicating an activated local cardiac ET system and possibly a reduced postreceptor signaling efficiency.

Aequorin↗

PubMed1999

Relationship between Na+-Ca2+-exchanger protein levels and diastolic function of failing human myocardium.

BACKGROUND: In the failing human heart, sarcoplasmic reticulum (SR) calcium handling is impaired, and therefore, calcium elimination and diastolic function may depend on the expression of sarcolemmal Na+-Ca2+ exchanger. METHODS AND RESULTS: Force-frequency relations were studied in ventricular muscle strip preparations from failing human hearts (n=29). Protein levels of Na+-Ca2+ exchanger and SR Ca2+-ATPase were measured in the same hearts. Hearts were divided into 3 groups by discriminant analysis according to the behavior of diastolic function when stimulation rate of muscle strips was increased from 30 to 180 min-1. At 180 compared with 30 min-1, diastolic force was increased by 160%, maximum rate of force decline was decreased by 46%, and relaxation time was unchanged in group III. In contrast, in group I, diastolic force and maximum rate of force decline did not change, and relaxation time decreased by 20%. Na+-Ca2+ exchanger was 66% higher in group I than in group III. Na+-Ca2+ exchanger was inversely correlated with the frequency-dependent rise of diastolic force when stimulation rate was increased (r=-0.74; P<0.001). Compared with nonfailing human hearts (n=6), SR Ca2+-ATPase was decreased and Na+-Ca2+ exchanger unchanged in group III, whereas Na+-Ca2+ exchanger was increased and SR Ca2+-ATPase unchanged in group I. Results with group II hearts were between those of group I and group III hearts. CONCLUSIONS: By discriminating failing human hearts according to their diastolic function, we identified different phenotypes. Disturbed diastolic function occurs in hearts with decreased SR Ca2+-ATPase and unchanged Na+-Ca2+ exchanger, whereas increased expression of the Na+-Ca2+ exchanger is associated with preserved diastolic function.

Adult↗

PubMed1998

Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium.

BACKGROUND: Levosimendan was shown to increase calcium sensitivity by a novel mechanism and to inhibit phosphodiesterase III activity in animal myocardium. METHODS AND RESULTS: We investigated the influence of levosimendan on isometric contractions and calcium transients (aequorin method) in muscle strips from human hearts with end-stage failing dilated or ischemic cardiomyopathy (n=27). Data were compared with the effects of the phosphodiesterase inhibitor milrinone (n=9). The average maximum increase in twitch tension was 47+/-14% (range, 6% to 150%) at a levosimendan concentration of 0. 8+/-0.3 micromol/L (P<0.01). This was associated with significant increases in maximum rates of tension rise and fall and decreases in times to peak tension, to 50% relaxation, and to 95% relaxation. In aequorin-loaded muscles, levosimendan 10(-6) mol/L increased average tension by 50% (P<0.02), associated with a nonsignificant increase in aequorin light (16%). With milrinone 10(-5) mol/L, average tension increased by 58% and aequorin light by 49% (P<0.05). In those muscle strips with pronounced inotropic effects (>50% increase in tension), there was a comparable and pronounced increase in aequorin light with both agents. However, in muscle strips with weak inotropic responses (<50% increase in tension), the increase in light was significantly higher with milrinone than with levosimendan. CONCLUSIONS: Levosimendan has inotropic and lusitropic actions in failing human myocardium. Comparison with the phosphodiesterase inhibitor milrinone indicates that in case of pronounced inotropic stimulation, the modes of action of the two agents may be similar (phosphodiesterase inhibition), whereas small inotropic effects of levosimendan may result predominantly from calcium sensitization.

Calcium↗

PubMed1998

Nucleotide-evoked relaxation of human coronary artery.

Endothelium-dependent dilation of coronary blood vessels in response to ATP and related nucleotides has been demonstrated in various animal species. The aim of the present study was to investigate a possible relaxant effect of ATP, the adenine nucleotides 2-methylthio ATP (MeSATP) and adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS), and the pyrimidine nucleotide UTP in isolated human coronary artery. In endothelium-intact rings of human coronary artery precontracted with K+ (20-40 mM), the nucleotides caused relaxation. Average maximal percentage relaxations and average EC50 values (concentrations causing half-maximal relaxation) were 89% and 47.1 microM for ATP, 28% and 0.3 microM for MeSATP, 35% and 0.6 microM for ADPbetaS, and 49% and 1.6 microM for UTP. For each of the four agonists, the potency to elicit relaxation varied greatly between individual rings, so that equi-relaxing concentrations spanned several orders of magnitude. Moreover, the sensitivities to ATP and UTP, when tested in the same ring, were not correlated. Mechanical removal of the endothelium as well as NG-nitro-L-arginine methyl ester (L-NAME; 30 microM), an inhibitor of nitric oxide synthase, abolished the relaxation caused by MeSATP, ADPbetaS and UTP and greatly attenuated the response to lower concentrations of ATP (3.2-320 microM), but high concentrations of ATP (320 and 1000 microM) caused relaxation also in endothelium-denuded preparations and in the presence of L-NAME. High concentrations of ADPbetaS (32 and 100 microM) and UTP (320 and 1000 microM) caused contraction of endothelium-denuded preparations. Thus, extracellular nucleotides cause endothelium-dependent, primarily nitric oxide-mediated relaxation of human coronary artery. ATP in addition causes endothelium-independent relaxation. The receptors activated by the nucleotides appear to be unevenly distributed on the coronary endothelium.

Adenosine Diphosphate↗

PubMed1998

Sarcoplasmic reticulum proteins in heart failure.

Altered calcium homeostasis may play a key role in the pathophysiology of human heart failure. Levels of sarcoplasmic reticulum (SR) proteins and sarcolemmal Na(+)-Ca2+ exchanger were analyzed by Western blot in failing and nonfailing human myocardium and related to myocardial function. Levels of the SR calcium release channel and of calcium storage proteins (calsequestrin and calreticulin) were not different in nonfailing and failing hearts. However, proteins involved in calcium removal were significantly altered in the failing human heart: (1) SR-Ca(2+)-ATPase levels and the ratio of SR-Ca(2+)-ATPase to its inhibitory protein phospholamban were significantly decreased, and (2) Na(+)-Ca2+ exchanger levels and the ratio of Na(+)-Ca2+ exchanger to SR-Ca(2+)-ATPase were significantly increased. SR-Ca(2+)-ATPase levels were closely correlated to systolic function as evaluated by frequency potentiation of contractile force. The frequency-dependent rise of diastolic force was inversely correlated with protein levels of Na(+)-Ca2+ exchanger. These findings indicate that altered expression of SR-Ca(2+)-ATPase and Na(+)-Ca2+ exchanger is relevant for altered systolic and diastolic function in human heart failure.

Animals↗

PubMed1998

Frequency-dependent changes in contribution of SR Ca2+ to Ca2+ transients in failing human myocardium assessed with ryanodine.

We tested the influence of blocking sarcoplasmic reticulum (SR) function with ryanodine (1 microM) on stimulation rate-dependent changes of intracellular Ca2+ transients and twitch force in failing human myocardium. Isometrically contracting, electrically stimulated muscle strips from ventricles of 10 end-stage failing human hearts were used. Muscles were loaded with the intracellular Ca2+ indicator aequorin. At stimulation rates from 0.5-3 Hz, intracellular Ca2+ transients and twitch force were simultaneously recorded before and after ryanodine exposure (37 degrees C). Ryanodine significantly reduced twitch force at 1 Hz by 46 +/- 9% and aequorin light by 57 +/- 10% in failing human myocardium (P < 0.05). The blunted or inverse aequorin light- and force-frequency relation became positive after ryanodine: in failing human myocardium, twitch force and aequorin light before ryanodine did not increase with increasing frequency and force decreased significantly at 3 Hz (P < 0.05). After ryanodine, twitch force (P < 0.05) and aequorin light increased with increasing stimulation frequency and were maximum at 2 Hz. The data indicate that inhibition of SR function significantly reduces twitch force and Ca2+ transients in failing human myocardium, but converts the blunted or inverse Ca(2+)- and force-frequency relation into a positive one. We infer that Ca2+ responsible for approximately 50% of twitch force is derived from the SR and approximately 50% from sarcolemmal Ca2+ influx in failing human myocardium. This sarcolemmal component increases at higher stimulation frequencies.

Calcium↗

PubMed1998

Frequency-dependence of myocardial energetics in failing human myocardium as quantified by a new method for the measurement of oxygen consumption in muscle strip preparations.

Diastolic dysfunction at high heart rates may be associated with increased myocardial energy consumption. Frequency-dependent changes of isometric force and oxygen consumption (MVO2) were investigated in strip preparations from endstage failing human hearts exhibiting various degrees of diastolic dysfunction. MVO2 was determined by a new method which was validated. When stimulation rate was increased from 40 to 200 min-1 (n=7), developed force decreased from 16.5+/-4.3 to 7.9+/-2.9 mN/mm2 (P<0.01), diastolic force increased from 15.9+/-3.2 to 22.0+/-3.0 mN/mm2 (P<0.01), and total MVO2 increased from 2.6+/-0.6 to 4.7+/-0.9 ml/min/100 g (P<0.025). Resting MVO2 and resting force were 1.8+/-0.4 ml/min/100 g and 15.9+/-3.0 mN/mm2, respectively. After addition of 30 mm 2,3-butanedione monoxime (BDM) to inhibit crossbridges, resting MVO2 and resting force decreased by 46% (P<0.05) and 15% (P<0.01), respectively, indicating the presence of active force generation in unstimulated failing human myocardium. In each muscle preparation, there was a significant correlation between force-time integral (FTI) and total MVO2 (r=0.96+/-0.01). The strength of these correlations did not vary with the contribution of diastolic FTI to total FTI. The ratio of activity related MVO2 to developed FTI, an inverse index of the economy of contraction, increased depending on the rise of diastolic FTI at higher stimulation rates. In conclusion, in failing human myocardium, diastolic force development is occurring at the same energy expenditure as systolic force generation. Therefore, in muscle preparations with disturbed diastolic function economy of contraction decreases with higher stimulation rates, depending on the rise of diastolic force.

Biomechanical Phenomena↗

PubMed1998

A mechanistic analysis of the force-frequency relation in non-failing and progressively failing human myocardium.

This review focuses on the role of the myocardial force-frequency relation (FFR) in human ventricular performance and how changes in the FFR can reduce cardiac output and, ultimately, can contribute to altering the stability of the in-vivo cardiovascular system in a way that contributes to the progression of heart failure. Changes in the amplitude, shape, and position of the myocardial FFR occurring in various forms of heart failure are characterized in terms of maximal isometric twitch tension, slope of the ascending limb (myocardial reserve), and position of the peak of the FFR on the frequency axis (optimum stimulation frequency). All three of these parameters decline according to severity of myocardial disease in the following order: non-failing atrial septal defect, non-failing coronary artery disease, non-failing coronary artery disease with diabetes mellitus, failing mitral regurgitation, failing viral myocarditis, failing idiopathic dilated cardiomyopathy. Evidence is presented supporting a sarcoplasmic reticulum Ca-pump based mechanism for this progressive depression of the FFR. Intracellular calcium cycling and concentration and Ca-pump content all diminish in proportion to degree of depression of the FFR. Additional evidence from myocyte culture studies suggests a cause of diminished Ca-pump content is sustained, elevated levels of plasma norepinephrine. A hypothesis is presented to explain the mechanism of myocardial failure and its progression in terms of changes in the cardiovascular feedback control system that are triggered by reduced myocardial reserve. Sustained elevation of plasma norepinephrine levels depresses expression of sarcoplasmic reticulum Ca-pump protein causing depression of the FFR and this causes a compensatory further increase in norepinephrine levels and a further depression of Ca-pump protein.

Biomechanical Phenomena↗

PubMed1998

Influence of SR Ca(2+)-ATPase and Na(+)-Ca(2+)-exchanger on the force-frequency relation.

The data presented indicate that altered systolic and diastolic function in failing human hearts may result from altered expression of calcium cycling proteins. Decreased systolic force production and inversion of the force-frequency relation seem to be related to reduced protein levels of SR Ca2+ ATPase and/or to increased protein levels of the Na(+)-Ca2+ exchanger resulting in an increased ratio of Na(+)-Ca2+ exchanger to SR Ca2+ ATPase. Impaired diastolic function may result from reduced SR Ca2+ ATPase and is most pronounced in failing hearts with lack of upregulation of the Na(+)-Ca2+ exchanger. Thus, failing hearts with reduced SR Ca2+ ATPase protein levels and unchanged Na(+)-Ca2+ exchanger protein levels exhibit severe impairment of both systolic and diastolic function.

Biomechanical Phenomena↗

PubMed1998

Influence of forskolin on the force-frequency behavior in nonfailing and end-stage failing human myocardium.

UNLABELLED: End-stage failing human myocardium is characterized by a negative force-frequency relationship (FFR), possibly as a result of reduced SR Ca2+ uptake capacity. We investigated the effects of the direct adenylate cyclase stimulator, forskolin, on force of contraction and FFR in isolated human myocardium from 7 nonfailing hearts (NF) and end-stage failing hearts (NYHA IV) due to either ischemic (ICM; n = 13) or dilated cardiomyopathy (DCM; n = 16). METHODS: Isolated left ventricular muscle strips, isometric contraction, electrical stimulation at a basal stimulation rate of 1 Hz (37 degrees C). Inotropic responses: Cumulative concentration-response curves for forskolin (0.01-10 microM) and for Ca2+ (2.5-15 mM). Force-frequency experiments: stepwise increase in stimulation rate from 0.5 to 3.0 Hz without and in the presence of 0.3, 1.0 or 3.0 microM forskolin. RESULTS: Forskolin concentration-dependently increased force of contraction to 386 +/- 28% (n = 5) in NF, to 256 +/- 48% (n = 7) in ICM, and to 212 +/- 13% (n = 14) in DCM. The effectiveness of forskolin was significantly reduced in failing myocardium. Ca2+ increased force of contraction to maximally 438 +/- 108% in NF, to 267 +/- 15% in ICM, and to 292 +/- 20% in DCM. Again, the effectiveness of Ca2+ was significantly reduced in failing myocardium. Forskolin activated contractile reserve to similar extents in all types of myocardium (90%, 95%, and 82%, respectively). Force of contraction continuously increased with increasing stimulation rates in nonfailing myocardium (positive FFR), but was blunted or inversed in ICM and DCM. Prestimulation with forskolin (0.3 microM) further enhanced frequency-potentiation in nonfailing, and normalized the slope and optimum stimulation frequency in ICM and DCM. However, at higher concentrations of forskolin, FFR was blunted or inversed in non-failing myocardium, and further impaired in failing myocardium. CONCLUSION: Low concentrations of forskolin with only marginal inotropic effects may partially normalize the inverse force-frequency relation in end-stage failing human myocardium. Reduced cAMP levels in conjunction with reduced expression of SR Ca2+ ATPase may be the underlying cause for altered excitation-contraction coupling in diseased human hearts.

Biomechanical Phenomena↗

PubMed1998

Shortening versus isometric contractions in isolated human failing and non-failing left ventricular myocardium: dependency of external work and force on muscle length, heart rate and inotropic stimulation.

BACKGROUND: For reasons of simplicity, studies on isolated human myocardium have been conducted using exclusively isometric contractions, although positive inotropic interventions may differently influence force development, extent of shortening and myocardial work performance. We investigated human left ventricular failing and non-failing preparations comparing isometric versus isotonic, i.e., shortening contractions. RESULTS: (1) When muscle length is increased from 90% to 100% lMAX, peak developed force increases by 36% and 43% (p < 0.05) in non-failing and failing human left ventricular myocardium, respectively. Maximum performed work increases similarly in non-failing but decreases in failing myocardium. It can be shown that this discrepancy is due to significantly higher resting tension and does not present an insufficient intrinsic shortening capacity in failing myocardium. (2) When stimulation rate is increased from 0.5 to 2.0 Hz, isometric force increases significantly by 59% in non-failing and decreases by 27% in failing myocardium, whereas maximum performed work increases by 98% and decreases by 46%, respectively. (3) Pharmacological positive inotropic interventions by 7.2 mM calcium (n = 9), 3 x 10(-8) M isoproterenol (n = 7), 3 x 10(-8) M ouabain (n = 5), and 10(-5) M EMD 57033 (n = 3) equally increased force development and extent of shortening: When the fractional effect on shortening (y) was correlated to the fractional effect on force (x), the following linear regression equation was obtained: y = 0.91x + 0.26 (r = 0.86; p < 0.001). CONCLUSIONS: The data presented are of clinical and pharmacological importance: (1) The Frank-Starling mechanism is demonstrated to be existent in the failing human myocardium regarding both isometric force developed and maximum work performed. (2) Both force-frequency relations and--to a greater extent--work-frequency relations are reversed in failing human myocardium. (3) Independent of the pharmacological mode of action, positive inotropic compounds increase developed isometric force to the same extent as isotonic shortening and therefore potentiate maximum performed work.

Adolescent↗

PubMed1998

Effects of left ventricular hypertrophy on force and Ca2+ handling in isolated rat myocardium.

To study the effect of left ventricular (LV) hypertrophy on force and Ca2+ handling in isolated rat myocardium, LV hypertrophy was induced in rats by banding of the abdominal aorta. After 16 wk, arterial pressure was assessed by catheterization. LV trabeculae were isolated and loaded with indo 1 salt by iontophoretic injection. Isometric force and intracellular free Ca2+ concentration ([Ca2+]i) were measured at stimulation frequencies between 0.25 and 3 Hz and rest intervals between 2 and 240 s. Sarcoplasmic reticulum (SR) Ca2+ content was also investigated using rapid cooling contractures (RCC). Systolic and diastolic pressure as well as heart weight-to-body weight ratios were significantly elevated in banded compared with control animals (167 vs. 117 mmHg, 108 vs. 83 mmHg, and 4.6 vs. 4.0 mg/g, respectively). At high frequencies, twitch relaxation and [Ca2+]i decline rates were significantly slower in banded compared with control rats, and diastolic [Ca2+]i was higher in the banded rat muscles (at 3 Hz, force half-time = 83 vs. 68 ms; time constant of [Ca2+]i decline = 208 vs. 118 ms; and diastolic [Ca2+]i = 505 vs. 353 nM). These differences could not be ascribed to altered Na+/Ca2+ exchange, since twitch relaxation and Ca2+ handling were not different between groups in the presence of caffeine (or cyclopiazonic acid plus ryanodine), where relaxation depends primarily on Na+/Ca2+ exchange. After long rest intervals (> or = 120 s), control rats showed a significant rest potentiation of force and Ca2+ transients, whereas banded rats did not. In addition, RCC amplitudes increased with rest in control but were unaltered in banded rats. In summary, pressure-overload hypertrophy was associated with slower twitch relaxation and [Ca2+]i decline but also with blunted rest potentiation of twitches and SR Ca2+ content of LV trabeculae. The decrease in SR Ca(2+)-ATPase function in banded rats may contribute to the observed diastolic dysfunction associated with pressure-overload hypertrophy.

Animals↗

PubMed1998

[New aspects of the pathophysiology of heart failure].

The progression of heart failure is related to activation of neuroendocrine hormone systems. On the level of the myocardium, they contribute to hypertrophy, dilation and remodeling of the ventricles. In addition, vascular alterations with endothelial dysfunction and alterations of skeletal muscle contribute to clinical symptoms of heart failure patients. Changes in ventricular geometry during the progression of cardiac diseases are associated with specific subcellular alterations on the level of the myocytes. Especially, disturbed intracellular Ca2+ handling resulting in altered excitation contraction coupling may lead to impaired systolic and diastolic function. Disturbed Ca2+ homeostasis has been associated with reduced re-uptake capacity of the sarcoplasmic reticulum for Ca2+ and an enhanced activity of the sarcolemmal Na+/Ca2+ exchange. In consequence, alterations in force-frequency behavior were attributed to a decline in intracellular Ca2+ transients at higher stimulation rates. The reduced expression of myocardial beta-adrenoceptors and alterations on the level of the G-proteins result in a reduced activity of adenylate cyclase and reduction in intracellular cAMP content of the myocytes. In consequence, reduced phosphorylation of intracellular functional proteins in the failing human heart contributes to altered Ca2+ handling. The Frank-Starling-mechanism seems to be unaltered in failing isolated human myocardium. Endothelin and angiotensin may contribute to the regulation of myocardial contractility in the human heart, but their functional relevance in the regulation of myocardial contractility under clinical conditions remains to be evaluated.

Animals↗

PubMed1997

Ca(2+)-dependent and Ca(2+)-independent regulation of contractility in isolated human myocardium.

UNLABELLED: Changes in contractile force of the myocardium may depend on changes in the intracellular Ca2+ concentration, changes in the responsiveness of the myofibrils for Ca2+, or a combination of both. We investigated in isolated muscle strip preparations from human nonfailing and endstage failing hearts the influence of physical (changes in preload, stimulation rate, or rhythm), and pharmacological interventions (alpha- or beta-adrenoceptor-stimulation, endothelin) on developed force of contraction and the corresponding intracellular Ca2+ transients. METHODS: Isometric contraction, electrical stimulation, 37 degrees C. Simultaneous registration of force of contraction and intracellular Ca2+ transients (aequorin method). RESULTS: Increases in preload, alpha- and endothelin-receptor stimulation resulted in increases in force of contraction without increasing aequorin light emission. Increasing stimulation rate or increasing rest intervals resulted in parallel increases (nonfailing myocardium) or decreases (failing myocardium) of force of contraction and aequorin light emission. beta-Adrenoceptor-stimulation exerted inotropic and lusitropic effects in human failing myocardium associated with a large, overproportional increase in aequorin light emission. CONCLUSION: The human heart regulates intrinsic contractility via several subcellular mechanisms. Increases in preload (Frank-Starling-mechanism) and alpha- or endothelin-receptor-stimulation enhance myocardial contractility by increasing the Ca2+ responsiveness of the myofilaments; rate- and rhythm-dependent modulation of the contractile state directly depend on changes in the intracellular Ca(2+)-transients; beta-adrenoceptor stimulation results in an overproportional large increase in intracellular Ca2+ transients, probably due to additional cAMP-dependent Ca(2+)-desensitizing effects on the level of the myofibrils.

Calcium↗

PubMed1997

Calcium handling proteins in the failing human heart.

There is accumulating evidence that disturbed calcium homeostasis may play a key role in the pathophysiology of human heart failure. Because disturbed calcium handling could result from altered protein expression, levels of calcium handling proteins were quantitated by Western Blot analysis in failing and nonfailing human myocardium from hearts with endstage failing dilated or ischemic cardiomyopathy. Protein levels of the sarcoplasmic reticulum calcium release channel (ryanodine receptor) and of calcium storage proteins (calsequestrin and calreticulin) were similar in failing and nonfailing human myocardium. However, proteins involved in calcium removal from the cytosol were significantly altered in the failing human heart: 1) SR-Ca(2+)-ATPase, relevant for removal of calcium from the cytosol into the lumen of the sarcoplasmic reticulum, was decreased; 2) phospholamban, which inhibits the SR-Ca(2+)-ATPase in the basal unphosphorylated state, was slightly decreased; 3) the ratio of SR-Ca(2+)-ATPase to phospholamban was decreased; 4) the sarcolemmal Na(+)-Ca(2+)-exchanger, relevant for transsarcolemmal calcium extrusion was increased in the failing hearts. In summary, altered levels of proteins involved in calcium removal from the cytosol suggest an increase in transsarcolemmal calcium elimination relative to sarcoplasmic reticulum calcium removal. These findings support the concept that reduced function of the sarcoplasmic reticulum to accumulate calcium may reflect a major defect in excitation-contraction coupling in human heart failure.

Calcium↗

PubMed1997

Influence of stimulation frequency on [Na+]i and contractile function in Langendorff-perfused rat heart.

To study the relationship between stimulation frequency and intracellular Na+ concentration ([Na+]i), Langendorff-perfused rat hearts were loaded with the Na(+)-sensitive dye sodium-binding benzofuran isophthalate (SBFI). An intracellular calibration procedure allowed SBFI fluorescence to be transformed into [Na+]i. Compartmentation of SBFI was evaluated by permeabilizing sarcolemmal membranes with saponin and subcellular compartments with Triton X-100. Most of the indicator was located in the myoplasm (69%). When stimulation frequency was increased from 0 to 6 Hz, [Na+]i increased from 3.0 to 7.9 mM, whereas pressure amplitude (PA) declined to 49% of the maximum recorded at 2 Hz. Blocking sarcoplasmic reticulum (SR) Ca2+ uptake with 2,5-di(tert-butyl)-1,4-benzohydroquinone (TBQ; 10 microM) at 2 Hz increased [Na+]i from 4.9 to 8.4 mM and decreased PA by 70%. Raising stimulation frequency then resulted in a further increase in [Na+]i and decline in PA. In conclusion, these data indicate that the rat heart is characterized by a negative pressure-frequency relationship associated with increasing [Na+]i at higher heart rates. After inhibition of SR Ca2+ uptake, [Na+]i further increases, whereas PA declines with increasing stimulus frequency. It is suggested that part of the rise of [Na+]i with stimulus frequency and TBQ may be associated with increased Ca2+ extrusion and Na+ influx on the Na+/Ca2+ exchange system.

Action Potentials↗

PubMed1996

Existence of the Frank-Starling mechanism in the failing human heart. Investigations on the organ, tissue, and sarcomere levels.

BACKGROUND: The Frank-Starling mechanism is one of the most important physiological principles for regulation of contractile performance. We therefore studied the question of whether this mechanism may be absent or attenuated in end-stage failing human left ventricular myocardium. METHODS AND RESULTS: Different methodological approaches were used to analyze the effects of this mechanism on the organ, tissue, and sarcomere levels: (1) In excised human whole left ventricles (2 donor hearts, 5 failing hearts), diastolic and systolic pressure-volume relationships were obtained. (2) In isolated muscle strip preparations from the left ventricular wall of donor hearts (n = 14) and failing hearts from patients with idiopathic dilated cardiomyopathy (n = 21) and ischemic cardiomyopathy (n = 11), peak developed force was measured at different muscle lengths of the preparation. (3) Skinned fiber preparations were obtained from failing right and left ventricles (n = 12). In all three studies, we clearly observed the existence of the Frank-Starling mechanism: (1) In isolated failing human left ventricles, peak developed isometric pressure is increased when the preload is elevated. (2) Peak developed tension is increased by approximately 50% to 70% (P < .01) in left ventricular preparations of failing and nonfailing ventricles when the muscles are stretched from 90% to 100% optimum length. (3) An increase in sarcomere length leads to a sensitization of contractile proteins of ventricular skinned fiber preparations from failing human hearts. At 1.9-microns sarcomere length, the EC50 value was 5.56 +/- 0.06, and at 2.3 microns it was 5.70 +/- 0.05 (P < .01; n = 7). CONCLUSIONS: The Frank-Starling mechanism is maintained in end-stage failing human hearts, whereas significant alterations of diastolic myocardial distensibility are evident in chronic heart failure.

Analysis of Variance↗