Customized 3D radiographic reconstruction of the human pelvis

BACKGROUND: In patients with chronic heart failure (CHF), plasma endothelin-1 (ET-1) levels are increased. We studied whether the cardiac ET-receptor system is altered in CHF patients. METHODS AND RESULTS: We assessed ET-evoked inositol phosphate (IP) formation in slices from right atria and left ventricles from 6 potential heart transplant donors (NFH) and 15 patients with end-stage CHF; in membranes from the same tissues, we studied ET-induced inhibition of isoprenaline- and forskolin-stimulated adenylyl cyclase and ET-receptor density. ET (10[-9] to 10[-6] mol/L, ET-1 > ET-3) increased IP formation in right atria and left ventricles through ET(A)-receptor stimulation in a concentration-dependent manner; no difference in potency or efficacy between NFH and CHF hearts was observed. ET-1 (10[-10] to 10[-6] mol/L), via ET(A)-receptor stimulation, inhibited isoprenaline- and forskolin-stimulated adenylyl cyclase in right atria but not in left ventricles, whereas carbachol inhibited adenylyl cyclase in both tissues; again, the potency and efficacy of ET- or carbachol-induced adenylyl cyclase inhibition was not different between NFH and CHF hearts. [125I]ET-1 binding revealed the coexistence of ET(A) and ET(B) receptors in both tissues; however, the density of ET(A) receptors was not significantly different between NFH and CHF hearts. Finally, the immunodetectable amount of left ventricular Gq/11 protein did not differ between NFH and CHF hearts. CONCLUSIONS: In the human heart, ET(A) and ET(B) receptors coexist; however, only ET(A) receptors are of functional importance. In right atria, ET(A) receptors couple to IP formation and inhibition of adenylyl cyclase; in left ventricles, they couple only to IP formation. In end-stage CHF, the functional responsiveness of the cardiac ET(A)-receptor system is not altered.     

Diminished responsiveness of Gs-coupled receptors in severely failing human hearts: no difference in dilated versus ischemic cardiomyopathy

In end-stage heart failure, cardiac beta-adrenoceptors are decreased and cardiac Gi protein is increased. We assessed beta-adrenoceptors, G proteins, and effects of several beta-adrenoceptor agonists, histamine, and 5-HT on adenylyl cyclase activity in right and left atria and left ventricles and on left ventricular contractility in six potential heart transplant donors (nonfailing hearts; NFHs) and in nine patients with end-stage dilated cardiomyopathy (DCM) and 11 patients with end-stage ischemic cardiomyopathy (ICM) to establish whether the functional responsiveness of all cardiac Gs-coupled receptors is reduced. Beta-adrenoceptors were reduced in all three tissues; in DCM, beta1-adrenoceptors were more markedly downregulated; in ICM, both beta1- and beta2-adrenoceptors were diminished. In all three tissues, isoprenaline-, terbutaline-, histamine- and 5-HT-induced adenylyl cyclase activation was reduced similarly in DCM and ICM. Moreover, in DCM and ICM, guanosine triphosphate (GTP)- (involving Gs and Gi) activated adenylyl cyclase was significantly diminished, whereas NaF-activated (involving only Gs) and Mn2+-activated (acting at the catalytic unit of the enzyme) adenylyl cyclase was unaltered. Left ventricular positive inotropic responses to beta1- (noradrenaline, dopamine, and dobutamine), beta2- (terbutaline), and beta1- and beta2-adrenoceptors (isoprenaline, adrenaline, and epinine), as well as H2-receptor (histamine) stimulation were significantly reduced. The extent of reduction was not different for each agonist in ICM and DCM. We conclude that in DCM and ICM, functional responsiveness of all cardiac Gs-coupled receptors is similarly reduced.     

Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium

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

Reduced beta 1 receptor messenger RNA abundance in the failing human heart

Heart failure in humans is characterized by alterations in myocardial adrenergic signal transduction, the most prominent of which is down-regulation of beta 1-adrenergic receptors. We tested the hypothesis that down-regulation of beta 1-adrenergic receptors in the failing human heart is related to decreased steady-state levels of beta 1 receptor mRNA. Due to the extremely low abundance of beta 1 receptor mRNA, measurements were possible only by quantitative polymerase chain reaction (QPCR) or by RNase protection methods. Because the beta 1 receptor gene is intronless and beta 1 receptor mRNA abundance is low, QPCR yielded genomic amplification in total RNA, and mRNA measurements had to be performed in poly (A)(+)-enriched RNA. By QPCR the concentration of beta 1 receptor mRNA varied from 0.34 to 7.8 x 10(7) molecules/microgram poly(A)(+)-enriched RNA, and the assay was sensitive to 16.7 zeptomol. Using 100-mg aliquots of left ventricular myocardium obtained from organ donors (nonfailing ventricles, n = 12) or heart transplant recipients (failing ventricles, n = 13), the respective beta 1 mRNA levels measured by QPCR were 4.2 +/- 0.7 x 10(7)/micrograms vs. 2.10 +/- 0.3 x 10(7)/micrograms (P = 0.006). In these same nonfailing and failing left ventricles the respective beta 1-adrenergic receptor densities were 67.9 +/- 6.9 fmol/mg vs. 29.6 +/- 3.5 fmol/mg (P = 0.0001). Decreased mRNA abundance in the failing ventricles was confirmed by RNase protection assays in total RNA, which also demonstrated a 50% reduction in beta 1 message abundance. We conclude that down-regulation of beta 1 receptor mRNA contributes to down-regulation of beta 1 adrenergic receptors in the failing human heart.     

Analysis of right ventricular function during bypass of the left side of the heart by afterload alterations in both normal and failing hearts

This study investigated the mechanism of right ventricular failure during bypass of the left side of the heart by precisely assessing right ventricular function with use of a conductance catheter. Bypass of the left side of the heart was established with a centrifugal pump in 10 mongrel dogs weighing 11 to 19 kg. Right ventricular function during left heart bypass was evaluated by two parameters that were both derived from measurement of relative change in right ventricular volume by the conductance catheter technique. One parameter was the right ventricular end-systolic pressure-volume relationship as a load-independent index, and the other was the peak right ventricular pressure-right ventricular stroke volume relationship as a "force-velocity relationship." These parameters were measured in both normal and failing hearts while afterload was increased by bilateral intrapulmonary balloon inflation. Moreover, changes in these relationships were observed by varying assist ratios of left heart bypass from 0% to 100%. Failing heart models were induced by normothermic aortic clamping for 20 minutes. The right ventricular end-systolic pressure-volume relationship in normal hearts did not change, irrespective of the assist ratio of left heart bypass, whereas that in failing hearts decreased from 4.25 +/- 1.41 mm Hg/ml without bypass of the left side of the heart to 3.53 +/- 1.30 mm Hg/ml after 100% assist of left heart bypass (p < 0.05). In the peak right ventricular pressure-right ventricular stroke volume relationship, right ventricular stroke volume was almost constant in normal hearts when afterload was increased regardless of the assist ratio of left heart bypass. Moreover, right ventricular stroke volume was maintained at a higher level during bypass of the left side of the heart compared with that without left heart bypass. However, that slope of the relationship in failing hearts was inversely linear and became significantly steeper after 100% assist of bypass of the left side of the heart compared with that without left heart bypass (-0.131 +/- 0.042 versus -0.051 +/- 0.038, p < 0.005). Therefore ++these two slopes of the relationship intersected at a point that was considered the critical point of afterload during bypass of the left side of the heart. In other words, right ventricular stroke volume was decreased by 100% left heart bypass above the critical point of afterload. In conclusion, this study demonstrates not only that bypass of the left side of the heart results in an increase in right ventricular stroke volume in both normal and failing hearts at the physiologic range of afterload, but also that right ventricular function against higher afterload is impaired by 100% assist of bypass of the left side of the heart in failing hearts.     

Myosin heavy chain gene expression in human heart failure

Two isoforms of myosin heavy chain (MyHC), alpha and beta, exist in the mammalian ventricular myocardium, and their relative expression is correlated with the contractile velocity of cardiac muscle. Several pathologic stimuli can cause a shift in the MyHC composition of the rodent ventricle from alpha- to beta-MyHC. Given the potential physiological consequences of cardiac MyHC isoform shifts, we determined MyHC gene expression in human heart failure where cardiac contractility is impaired significantly. In this study, we quantitated the relative amounts of alpha- and beta-MyHC mRNA in the left ventricular free walls (LVs) of 14 heart donor candidates with no history of cardiovascular disease or structural cardiovascular abnormalities. This group consisted of seven patients with nonfailing (NF) hearts and seven patients with hearts that exhibited donor heart dysfunction (DHD). These were compared with 19 patients undergoing cardiac transplantation for chronic end-stage heart failure (F). The relative amounts of alpha-MyHC mRNA to total (i.e., alpha + beta) MyHC mRNA in the NF- and DHD-LVs were surprisingly high compared with previous reports (33.3+/-18.9 and 35.4+/-16.5%, respectively), and were significantly higher than those in the F-LVs, regardless of the cause of heart failure (2.2+/-3.5%, P < 0.0001). There was no significant difference in the ratios in NF- and DHD-LVs. Our results demonstrate that a considerable amount of alpha-MyHC mRNA is expressed in the normal heart, and is decreased significantly in chronic end-stage heart failure. If protein and enzymatic activity correlate with mRNA expression, this molecular alteration may be sufficient to explain systolic dysfunction in F-LVs, and therapeutics oriented towards increasing alpha-MyHC gene expression may be feasible.     

Troponin I phosphorylation in the normal and failing adult human heart

BACKGROUND: In the failing human heart myofibrillar calcium sensitivity of tension development is greater and maximal myofibrillar ATPase activity is less than in the normal heart. Phosphorylation of the cardiac troponin I (cTnI)-specific NH2-terminus decreases myofilament sensitivity to calcium, while phosphorylation of other cTnI sites decreases maximal myofibrillar ATPase activity. METHODS AND RESULTS: We examined cTnI phosphorylation in left ventricular myocardium collected from failing hearts at the time of transplant (n=20) and normal hearts from trauma victims (n=24). The relative amounts of actin, tropomyosin, and TnI did not differ between failing and normal myocardium. Using Western blot analysis with a monoclonal antibody (MAb) that recognizes the striated muscle TnI isoforms, we confirmed that the adult human heart expresses only cTnI. A cTnI-specific MAb recognized two bands of cTnI, designated cTnI1 and cTnI2, while a MAb whose epitope is located in the cTnI-specific NH2-terminus recognized only cTnI1. Alkaline phosphatase decreased the relative amount of cTnl1, while protein kinase A and protein kinase C increased cTnI1. The percentage of cTnI made up of cTnI1, the phosphorylated form of TnI, is greater in the normal than the failing human heart (P<.00). CONCLUSIONS: This phosphorylation difference could underlie the reported greater myofibrillar calcium sensitivity of failing myocardium. The functional consequence of this difference may be an adaptive or maladaptive response to the lower and longer calcium concentration transient of the failing heart, eg, enhancing force development or producing ventricular diastolic dysfunction.     

Beta-adrenergic signal transduction in the failing and hypertrophied myocardium

A strong sympathetic activation has been observed in heart failure and is the cause of beta-adrenergic desensitization in this condition. On the receptor level there is downregulation of beta1-adrenergic receptors and uncoupling of beta2-adrenoceptors. The latter mechanism has been related to an increased activity and gene expression of beta-adrenoceptor kinase in failing myocardium, leading to phosphorylation and uncoupling of receptors. beta3-Adrenoceptors mediate negative inotropic effects, but alterations in these receptors are not known. In addition, an increase in inhibitory G protein alpha subunits (Gi alpha) has been suggested to be causally linked to adenylyl cyclase desensitization in heart failure. In contrast, the catalytic subunit of adenylyl cyclase, stimulatory G protein alpha and betagamma subunits, have been observed to be unchanged. Recent evidence shows that increases in Gi alpha also depress adenylyl cyclase in compensated cardiac hypertrophy both in monogenic and polygenic and in secondary hypertension. These increases of Gi alpha can suppress adenylyl cyclase in the absence of beta-adrenergic receptor downregulation. Since cardiac hypertrophy in pressure overload is a strong predictor of cardiac failure, these observations indicate that adenylyl cyclase desensitization by Gi alpha may be a pathophysiologically relevant mechanism contributing to the progression from compensated cardiac hypertrophy to heart failure.     

Thrombogenic and atherogenic lipid modifications in plasma and patients with coronary artery disease and after coronary artery bypass surgery

BACKGROUND: Although multiple studies have shown that the left ventricular assist device (LVAD) improves distorted cardiac geometry, the pathological mechanisms of the "reverse remodeling" of the heart are unknown. Our goal was to determine the effects of LVAD support on cardiac myocyte size and shape. METHODS AND RESULTS: Isolated myocytes were obtained at cardiac transplantation from 30 failing hearts (12 ischemic, 18 nonischemic) without LVAD support, 10 failing hearts that received LVAD support for 75+/-15 days, and 6 nonfailing hearts. Cardiac myocyte volume, length, width, and thickness were determined by use of previously validated techniques. Isolated myocytes from myopathic hearts exhibited increased volume, length, width, and length-to-thickness ratio compared with normal myocytes (P<0.05). However, there were no differences in any parameter between myocytes from ischemic and nonischemic cardiomyopathic hearts. Long-term LVAD support resulted in a 28% reduction in myocyte volume, 20% reduction in cell length, 20% reduction in cell width, and 32% reduction in cell length-to-thickness ratio (P<0.05). In contrast, LVAD support was associated with no change in cell thickness. These cellular changes were associated with reductions in left ventricular dilation and left ventricular mass measured echocardiographically in 6 of 10 LVAD-supported patients. CONCLUSIONS: These studies suggest that the regression of cellular hypertrophy is a major contributor to the "reverse remodeling" of the heart after LVAD implantation. The favorable alterations in geometry that occur in parallel fashion at both the organ and cellular levels may contribute to reduced wall stress and improved mechanical performance after LVAD support.     

Redox components and structure of the respiratory NADH:ubiquinone oxidoreductase (complex I)

Surgical ablation of extrinsic cardiac nerve fibers results in a chronically denervated state of the left ventricle of the heart. The present study was performed to elucidate the effect of a period of 5 weeks of chronic denervation on cardiac catecholamine levels in general and dopamine in particular. Moreover, the possible effect on cardiac beta-adrenoceptor subtypes was investigated. Experiments were performed on adult dogs. In addition to adrenaline and noradrenaline the tissue levels of dopamine were found to be severely depressed. A significant shift from beta1- to beta2-adrenoceptor subtype was observed, while the total beta-adrenoceptor density remained unaffected. The present findings indicate that catecholamine synthesis in chronically denervated hearts is impaired upstream of dopamine and that a shift in beta-adrenoceptor subtype occurs already within a relatively short period of five weeks of denervation, and suggest that the lack of endogenous catecholamines influence the relative expression levels of the two subtypes of beta-adrenoceptors present in cardiac tissue.     

UVB induces atypical melanocytic lesions and melanoma in human skin

OBJECTIVES: The purpose of the present study was to examine the expression of the endothelial-type nitric oxide synthase (NOS III) and the inducible-type NOS (NOS II) in human myocardium and their regulation in heart failure from patients with different etiologies. BACKGROUND: In heart failure, plasma levels of nitrates were found to be elevated. However, data on myocardial NOS expression in heart failure are conflicting. METHODS: Using RNase protection analysis and Western blotting, the expression of NOS III and NOS II was investigated in ventricular myocardium from nonfailing (NF) hearts (n=5) and from failing hearts of patients with idiopathic dilated cardiomyopathy (dCMP, n=14), ischemic cardiomyopathy (iCMP, n=9) or postmyocarditis cardiomyopathy (mCMP, n=7). Furthermore, immunohistochemical studies were performed to localize NOS III and NOS II within the ventricular myocardium. RESULTS: In failing human hearts, NOS III mRNA levels were increased to 180% in dCMP, 200% in iCMP and to 210% in mCMP as compared to NF hearts. Similarly, in Western blots (using constitutively expressed beta-tubulin as a reference) NOS III protein expression was increased about twofold in failing compared to NF hearts. Immunohistochemical studies with a selective antibody to NOS III showed no obvious differences in the staining of the endothelium of cardiac blood vessels from NF and failing human hearts. However, NOS III-immunoreactivity in cardiomyocytes was significantly more intense in failing compared to NF hearts. Low expression of NOS II mRNA was detected in only 2 of 30 failing human hearts and was not found in NF hearts. Inducible-type NOS protein was undetectable in either group. CONCLUSIONS: We conclude that the increased NOS III expression in the ventricular myocardium of failing human hearts may contribute to the contractile dysfunction observed in heart failure and/or may play a role in morphologic alterations such as hypertrophy and apoptosis of cardiomyocytes.     

Results of postmortem examination of psittacine birds with cardiac disease: 26 cases (1991-1995)

OBJECTIVE: To characterize prevalence and type of cardiac disease evident in psittacine birds during postmortem examination. DESIGN: Retrospective study. ANIMALS: 26 psittacine birds with gross and histologic evidence of cardiac disease. PROCEDURE: Records of postmortem examinations of psittacine birds necropsied during a 4-year period were reviewed. Data on gross and histologic evidence of cardiac disease were analyzed. Birds identified included those in which congestive heart failure (CHF) was considered the primary cause of death and those in which substantial cardiac disease was evident, despite a lack of postmortem findings supportive of CHF. RESULTS: Of 269 psittacine birds necropsied, 26 (9.7%) had evidence of cardiac disease. In 15 (58%) birds with cardiac disease, changes consistent with CHF were evident and were sufficiently severe as to be considered the cause of death. The remaining 11 birds had cardiac lesions secondary to other systemic diseases; cardiac lesions were considered to be an incidental finding in these birds, and CHF was not evident. Of the 15 birds with CHF, 10 had evidence of right ventricular or biventricular failure, whereas only 5 had evidence of left ventricular failure. CLINICAL IMPLICATIONS: Prevalence of cardiac disease in the psittacine birds reported here was similar to that seen clinically in other companion animals. The high incidence of right ventricular or biventricular heart failure in psittacine birds was similar to that for poultry in which lesions of right-sided heart failure predominate.     

Gross anatomy of the cardiac blood vessels in the North American beaver (Castor canadensis)

The cardiac arteries and veins are described in the North American beaver (Castor canadensis) following the injection of the vessels of 15 hearts with either latex, vinyl plastic or barium sulfate. The left coronary artery gives off the typical circumflex and paraconal interventricular branches which supply the left atrium and ventricle and part of the right ventricle and interventricular septum. The right coronary artery vascularizes the right atrium and ventricule and by means of its subsinuosal interventricular branch, part of the left ventricle and interventricular septum. The paraconal interventricular branch of the left coronary artery lies within the myocardium and is not visible on the surface of the heart. There are no intercoronary anastomoses between the right and left vessels. The major cardiac veins open into the terminal end of the left cranial vena cava. Unlike the arteries, there are venous anastomoses interconnecting the great cardiac vein and the middle cardiac vein. It is concluded that the cardiac blood vessels in Castor canadensis are typically mammalian and resemble those of both land and aquatic mammals.     

Remodeling of chick embryonic ventricular myoarchitecture under experimentally changed loading conditions

Adult myocardium adapts to changing functional demands by hyper- or hypotrophy while the developing heart reacts by hyper- or hypoplasia. How embryonic myocardial architecture adjusts to experimentally altered loading is not known. We subjected the chick embryonic hearts to mechanically altered loading to study its influence upon ventricular myoarchitecture. Chick embryonic hearts were subjected to conotruncal banding (increased afterload model), or left atrial ligation or clipping, creating a combined model of increased preload in right ventricle and decreased preload in left ventricle. Modifications of myocardial architecture were studied by scanning electron microscopy and histology with morphometry. In the conotruncal banded group, there was a mild to moderate ventricular dilatation, thickening of the compact myocardium and trabeculae, and spiraling of trabecular course in the left ventricle. Right atrioventricular valve morphology was altered from normal muscular flap towards a bicuspid structure. Left atrial ligation or clipping resulted in hypoplasia of the left heart structures with compensatory overdevelopment on the right side. Hypoplastic left ventricle had decreased myocardial volume and showed accelerated trabecular compaction. Increased volume load in the right ventricle was compensated primarily by chamber dilatation with altered trabecular pattern, and by trabecular proliferation and thickening of the compact myocardium at the later stages. A ventricular septal defect was noted in all conotruncal banded, and 25% of left atrial ligated hearts. Increasing pressure load is a main stimulus for embryonic myocardial growth, while increased volume load is compensated primarily by dilatation. Adequate loading is important for normal cardiac morphogenesis and the development of typical myocardial patterns.     

Technical considerations for partial left ventriculectomy (Batista operation)

The surgical technique for partial left ventriculectomy (Batista operation) as performed in two surgical centers is described. This surgical remodeling of the left ventricle restores the abnormal geometric configuration produced by the dilated failing heart. It accomplishes a reduction of the left ventricular end-diastolic diameter and end-diastolic volume with consequent increase in left ventricular function. This procedure represents the newest surgical approach in the management of patients with end-stage cardiomyopathy; it can be used as a bridge to transplantation or perhaps as a definitive form of therapy, particularly in those patients in whom heart transplantation is contraindicated. This report describes technical guidelines to avoid serious intraoperative and postoperative complications directly associated with this technique.     

Characterization of excitation-contraction coupling in conscious dogs with pacing-induced heart failure

OBJECTIVE: In isolated cardiac preparations of non-failing hearts from different species, including man, there is a positive force-frequency relation which is reversed into a negative relation in preparation from failing hearts. Whether or not such relations between ventricular function and heart rate hold true in the in situ heart is not clear at present. Mechanical restitution and postextrasystolic potentiation might serve as alternative measures of excitation-contraction coupling. METHODS: Eleven dogs were instrumented with a left ventricular micromanometer, ultrasonic crystals for the measurement of regional wall thickness, two hydraulic occluders around the descending aorta and the inferior caval vein, and left atrial and ventricular pacing leads with a subcutaneous pacemaker. Left ventricular dP/dtmax, as an isovolumic phase index, and systolic wall thickening, as an ejection phase index, were plotted versus heart rate, and heart rate was increased by left atrial pacing from rest to 200 min-1 in increments of 25 min-1. In a subset of dogs, left ventricular filling was controlled and the frequency range expanded by the bradycardic agent UL-FS 49. Measurements were performed in the presence and absence of autonomic blockade (hexamethonium, atropine). Mechanical restitution and postextrasystolic potentiation were determined as normalized dP/dtmax and systolic wall thickening, respectively, of the extra- and postextrasystolic beat versus defined variations of the extrasystolic time interval (250-550 ms). Following control studies, heart failure was induced by rapid left ventricular pacing at 250 min-1 for 20 days +/- 6 (SD) and measurements repeated. Isolated left ventricular trabeculae from non-failing and failing hearts were studied during stimulation at 0.2-4 Hz. RESULTS: Only with filling control and in the absence of autonomic blockade, was there a slightly positive relation between dP/dtmax and heart rate in the control state. Otherwise, the relation of dP/dtmax to heart rate was flat both in the control state and in heart failure. The relation between systolic wall thickening and heart rate in the control state was negative, unless filling was controlled, and it was flat in heart failure. In contrast, the time constants of mechanical restitution and postextrasystolic potentiation were increased significantly with heart failure from 91 +/- 25 (SD) to 164 +/- 13 ms and from 107 +/- 18 to 156 +/- 4 ms, respectively, for dP/dtmax and from 76 +/- 22 to 162 +/- 10 ms and from 101 +/- 17 to 160 +/- 17 ms, respectively, for systolic wall thickening. These time constants were, however, insensitive to UL-FS 49 and autonomic blockade. There was a negative force-frequency relation in left ventricular trabeculae from non-failing hearts at higher calcium concentrations, where it was flat in trabeculae from failing hearts. CONCLUSION: Time constants of mechanical restitution and postextrasystolic potentiation are more sensitive than the steady state relation of ventricular function and heart rate to characterize the impairment of excitation-contraction coupling in heart failure.     

Sarcoplasmic reticular Ca2+ pump ATPase activity in congestive heart failure due to myocardial infarction

OBJECTIVE: Earlier studies have shown a depression in the sarcoplasmic reticular (SR) Ca2+ uptake and gene expression in Ca2+ pump ATPase protein in congestive heart failure subsequent to myocardial infarction. It is the objective of this study to understand further the mechanisms of depressed SR Ca2+ pump activity in the failing heart. METHODS: Heart failure in rats was induced by occluding the left coronary artery for 16 weeks and the viable left ventricle was processed for the isolation of SR membranes. Sham-operated animals were used as control. The characteristics of SR Ca2+ pump ATPase in the presence of different concentrations of K+, Ca2+ and ATP were examined and the purity of these membranes was monitored by determining the marker enzyme activities. In addition to measuring changes in cyclic adenosine monophosphate (cAMP) protein kinase and Ca(2+)-calmodulin induced phosphorylation, alterations in SR phospholipid composition as well as sulfhydryl (SH) group content were investigated. RESULTS: Ca(2+)-stimulated ATPase activity, unlike Mg(2+)-ATPase activity, was depressed in the left ventricular SR from failing hearts as compared to control. The decrease in Ca(2+)-stimulated ATPase activity was seen at different concentrations of Ca2+, K+ and ATP but no changes in the affinities of the enzyme for Ca2+ and ATP were evident. The SR Ca(2+)-stimulated ATPase activities in the presence of both cAMP-dependent protein kinase and Ca(2+)-calmodulin were markedly decreased in the failing hearts when compared to control preparations. Furthermore, the 32P incorporation in the presence of cAMP-dependent protein kinase or Ca(2+)-calmodulin was also reduced in the experimental heart SR membranes. The phospholipid composition of the SR membranes from the failing heart was markedly altered. No changes in SH-group or the degree of cross contamination with other membranes were apparent in the failing heart SR. CONCLUSIONS: These results suggest that abnormalities in membrane phospholipid composition and phosphorylation of the enzyme may partly explain the observed depression in SR Ca2+ pump ATPase activity in heart failure following myocardial infarction.     

Decrease of cardiac chaos in congestive heart failure

The electrical properties of the mammalian heart undergo many complex transitions in normal and diseased states. It has been proposed that the normal heartbeat may display complex nonlinear dynamics, including deterministic chaos, and that such cardiac chaos may be a useful physiological marker for the diagnosis and management of certain heart trouble. However, it is not clear whether the heartbeat series of healthy and diseased hearts are chaotic or stochastic, or whether cardiac chaos represents normal or abnormal behaviour. Here we have used a highly sensitive technique, which is robust to random noise, to detect chaos. We analysed the electrocardiograms from a group of healthy subjects and those with severe congestive heart failure (CHF), a clinical condition associated with a high risk of sudden death. The short-term variations of beat-to-beat interval exhibited strongly and consistently chaotic behaviour in all healthy subjects, but were frequently interrupted by periods of seemingly non-chaotic fluctuations in patients with CHF. Chaotic dynamics in the CHF data, even when discernible, exhibited a high degree of random variability over time, suggesting a weaker form of chaos. These findings suggest that cardiac chaos is prevalent in healthy heart, and a decrease in such chaos may be indicative of CHF.