Search

Studies in the rapid-pacing model of heart failure have shown that left ventricular (LV) systolic function normalizes on cessation of pacing and LV diastolic dysfunction persists, but there is no information regarding atrial function under these conditions. To determine the effects of cessation of pacing on left atrial (LA) systolic and diastolic function, ten dogs with rapid pacing-induced heart failure (250 beats/min for 3-4 wk), six dogs with regression of heart failure (4 wk after cessation of rapid pacing), and seven control dogs were instrumented with LA sonomicrometers and micromanometers. At matched LA pressure, LA ejection (10.2 +/- 3.0 vs. 17.4 +/- 5.5%), reservoir volume fractions (19 +/- 8 vs. 35 +/- 11%), and heart rate-corrected mean normalized systolic ejection rate (1.25 +/- 0.33 vs. 1.60 +/- 0.44 EF/s) were significantly less, and the volume-normalized diastolic stiffness constant (4.9 +/- 0.8 vs. 3.2 +/- 1.1) was significantly greater, in regression versus control dogs; these changes were associated with incomplete regression of LA hypertrophy and a persistent 77.4% increase in beta-myosin heavy chain (beta-MHC) in the LA body. LV systolic function and weight were not significantly different, whereas the time constant of LV relaxation was longer (52.5 +/- 4.4 vs. 40.8 +/- 7.6 ms; P < 0.05) and LV end-diastolic pressure was greater (12.2 +/- 1.8 vs. 7.1 +/- 2.0 mmHg; P < 0.05) in regression compared with control dogs. Thus, unlike the normalization of LV systolic function observed with cessation of rapid pacing, LA systolic function is persistently abnormal, owing in part to persistent LV diastolic dysfunction, residual LA hypertrophy, and MHC isoform switches.

Background Many of the cardiovascular manifestations of thyroid hormone excess resemble those produced by sympathoadrenal stimulation. The objective of this study was to determine the effects of thyroid hormone excess on myocardial β-adrenergic expression and responsiveness to infused agonists in the primate heart. Methods and Results The responses of left ventricular isovolumic contraction (dP/dt max ) and relaxation (τ) during graded dobutamine infusion were studied both before and after 4 weeks of thyroid hormone administration in 8 chronically instrumented baboons. At matched (atrially paced) heart rates, thyroid hormone significantly increased resting dP/dt max (3073±1034 versus 2318±829 mm Hg/s, P P max and τ in response to β 1 -adrenergic stimulation was significant at each dobutamine dose (2.5 to 10 μg·kg −1 ·min −1 ), but when expressed as a percent change, it was similar before versus after thyroid hormone. Similar changes were found when β 2 -adrenergic stimulation was produced by terbutaline infusion in three additional baboons. β-Adrenergic receptor (βAR) expression was higher in five thyroxine-treated than in five control baboons (37.4±1.2 versus 15.7±3.2 fmol/mg, P 2 AR (5.9±1.5 to 20.6±1.2 fmol/mg, P 1 AR (9.7±1.7 to 16.8±0.1 fmol/mg, P Conclusions In the primate heart, thyroid hormone produces positive inotropic and lusitropic effects in the resting state and upregulates both β 1 AR and β 2 AR, with the β 2 AR increase predominating. At equivalent rates, however, thyroid hormone excess does not appear to enhance the sensitivity of left ventricular contractility and relaxation to either β 1 - or β 2 -adrenergic stimulation.

Primate alpha-chymases are mast cell neutral proteases that are involved in regulating several regulatory peptides including angiotensin II. Because of significant substrate specificity differences among the chymase group of enzymes, animal models that overexpress primate chymases are crucial for delineating the in vivo function of these enzymes. Activation of alpha-prochymase requires processing enzymes and proteoglycans found in mast cell secretory granules. Thus, the development of models overexpressing active primate chymase requires a mast cell-specific promoter. We show that the 571-base pair (bp) 5'-upstream sequence of the baboon chymase gene, which encodes an alpha-chymase, coupled to the prokaryotic lacZ gene allows the targeting of beta-galactosidase to mast cells in transgenic mice. Tissue expression of the transgene is similar to the expression of the endogenous mouse alpha-chymase mouse mast cell protease-5. A mouse mast cell line that endogenously expresses mouse mast cell protease-5 (JKras mast cells) also selectively supports the expression of this transgene. In vitro transcription studies in JKras mast cells shows the critical role of a GATA cis-regulatory motif in baboon chymase promoter, located approximately 430-bp upstream of the transcription start site. These results suggest that the 571-bp domain of the baboon chymase promoter contains most, if not all, of the mast cell-specific region of the promoter. We describe here for the first time a promoter that directs expression of transgenes specifically to mouse mast cells. This promoter should be generally applicable for dominant expression of mast cell regulatory proteins.

The transcriptional, posttranscriptional, and related functional effects of thyroid hormone on primate myocardium are poorly understood. Therefore, we studied the effects of thyroid hormone on sarcoplasmic reticulum (SR) Ca 2+ -cycling proteins and myosin heavy chain (MHC) composition at the steady state mRNA and protein level and associated alterations of left ventricular (LV) performance in 8 chronically instrumented baboons. The force-frequency and relaxation-frequency relations were assessed as the response of LV isovolumic contraction (dP/dt max ) and relaxation (Tau), respectively, to incremental atrial pacing. Both the heart rate at which dP/dt max was maximal and Tau was minimal (critical heart rates) in response to pacing were increased significantly after thyroid hormone. Postmortem LV tissue from 5 thyroid-treated and 4 additional control baboons was assayed for steady state mRNA levels with cDNA probes to MHC isoforms and SR Ca 2+ -cycling proteins. Steady state SR Ca 2+ -ATPase and phospholamban mRNA increased in the hyperthyroid state, and α-MHC mRNA appeared de novo, whereas β-MHC mRNA decreased. Western analysis (4 thyroid-treated and 4 control baboons) showed directionally similar changes in MHC isoforms and a slight increase in SR Ca 2+ -ATPase. In contrast, there was a statistically nonsignificant decrease in phospholamban protein, which resulted in a significant 40% decrease in the ratio of phospholamban to SR Ca 2+ -ATPase. Thus, thyroid hormone increases the transcription of Ca 2+ -cycling proteins and shifts MHC isoform expression in the primate LV. Our data suggest that both transcriptional and posttranslational mechanisms determine the levels of these proteins in the hyperthyroid primate heart and mediate, in part, the observed enhanced basal and frequency-dependent LV performance.

Phospholamban is the regulator of the cardiac sarcoplasmic reticulum (SR) Ca(2+)-ATPase activity and an important modulator of basal contractility in the heart. To determine whether all the SR Ca(2+)-ATPase enzymes are subject to regulation by phospholamban in vivo, transgenic mice were generated which overexpressed phospholamban in the heart, driven by the cardiac-specific alpha-myosin heavy chain promoter. Quantitative immunoblotting revealed a twofold increase in the phospholamban protein levels in transgenic hearts compared to wild type littermate hearts. The transgenic mice showed no phenotypic alterations and no changes in heart/body weight, heart/lung weight, and cardiomyocyte size. Isolated unloaded cardiac myocytes from transgenic mice exhibited diminished shortening fraction (63%) and decreased rates of shortening (64%) and relengthening (55%) compared to wild type (100%) cardiomyocytes. The decreases in contractile parameters of transgenic cardiomyocytes reflected decreases in the amplitude (83%) of the Ca2+ signal and prolongation (131%) in the time for decay of the Ca2+ signal, which was associated with a decrease in the apparent affinity of the SR Ca(2+)-ATPase for Ca2+ (56%), compared to wild type (100%) cardiomyocytes. In vivo analysis of left ventricular systolic function using M mode and pulsed-wave Doppler echocardiography revealed decreases in fractional shortening (79%) and the normalized mean velocity of circumferential shortening (67%) in transgenic mice compared to wild type (100%) mice. The differences in contractile parameters and Ca2+ kinetics in transgenic cardiomyocytes and the depressed left ventricular systolic function in transgenic mice were abolished upon isoproterenol stimulation. These findings indicate that a fraction of the Ca(2+)-ATPases in native SR is not under regulation by phospholamban. Expression of additional phospholamban molecules results in: (a) inhibition of SR Ca2+ transport; (b) decreases in systolic Ca2+ levels and contractile parameters in ventricular myocytes; and (c) depression of basal left ventricular systolic function in vivo.

Delayed traumatic pericardial syndromes are well recognized. We describe a case in which a patient presented 3 years after an initial trauma with manifestations of constrictive pericarditis. The etiology in this report is attributable to a large intrapericardial hematoma, which is rarely described. This article also illustrates the complimentary nature of magnetic imaging and Doppler echocardiography in the evaluation of pericardial disease.

An accurate noninvasive method for measuring the effects of pharmacologic agents on active relaxation of the left ventricle would provide a valuable tool for monitoring the treatment of diastolic heart failure related to coronary artery disease.The time constant of isovolumic relaxation (T) and the left atrioventricular gradient were measured with micromanometer catheters and diastolic left ventricular filling variables were measured with radionuclide ventriculography in nine anesthetized, open-chest dogs with an acute coronary artery occlusion. Infusion of the positive inotropic drug dobutamine hydrochloride (5 to 10 micrograms/kg/min) resulted in a 35% shortening of T and a 37% increase in the radionuclide first-half filling fraction (both p0.05), but no change in the left atrioventricular gradient. Conversely, infusion of the alpha-adrenergic vasoconstrictor phenylephrine hydrochloride (20 to 40 micrograms/min) augmented left ventricular load, increasing the atrioventricular gradient by 45%, but had no significant effect on T or the first-half filling fraction. Infusion of the direct-acting vasodilator, sodium nitroprusside (80 to 120 micrograms/min), was accompanied by a 14% lengthening of T with a corresponding 28% decrease in the first-half filling fraction (both p0.05).In an anesthetized, open-chest canine model of acute myocardial ischemia, the radionuclide first-half filling fraction reflects pharmacologically induced changes in the lusitropic state of the left ventricle with relative independence of loading conditions.

Abstract We evaluated the ability of M-mode and Doppler echocardiography to assess left ventricular (LV) function reliably and repeatedly in mice and tested whether these techniques could detect physiological alterations in phospholamban (PLB)–deficient mice. Anesthetized wild-type mice (n=7) and mice deficient in PLB (n=8) were studied with two-dimensional guided M-mode and Doppler echocardiography using a 9-MHz imaging and 5- to 7.5-MHz Doppler transducer. Data were acquired in the baseline state and after intraperitoneal isoproterenol administration (2.0 μg/g IP). Interobserver and intraobserver variability and reproducibility were excellent. PLB-deficient mice were associated with significant ( P 2 ), and peak early-diastolic transmitral velocity (80.0±7.2 versus 66.9±7.7 cm/s). LV dimensions, shortening fractions, heart rates, late diastolic transmitral (A) velocities, and early to late (E/A) diastolic velocity ratios were similar in both groups. Isoproterenol administration resulted in significant increases in Doppler indices of ventricular function in control but not PLB-deficient mice. These findings indicate that assessment of LV function can be performed noninvasively in mice under varying physiological conditions and that PLB regulates basal LV function in vivo.

Diastolic heart failure, in the absence of LV systolic dysfunction, is a common clinical condition that can be demonstrated in as many as one third of patients with congestive heart failure. Diastolic dysfunction caused by abnormalities in LV filling can be a result of many pathologic conditions, including hypertrophy, infiltrative cardiomyopathies, or myocardial ischemia. The major physiologic determinants of LV filling can be divided into cellular mechanisms, hemodynamic characteristics, and hormonal influences. Cellular mechanisms for impaired LV inactivation are determined by the handling of calcium within the myocyte during excitation-contraction-relaxation coupling. The hemodynamic characteristics of LV diastolic filling are determined by loading conditions, the time constant of isovolumic relaxation, heart rate, ventricular nonuniformity, pericardial restraint, myocardial elasticity, chamber compliance, and coronary blood flow. The sympathetic nervous system and the renin-angiotensin system are important modulators of diastolic filling, directly or indirectly. The diagnosis of heart failure is confirmed by a combination of clinical tests including invasive and noninvasive techniques, each of which has advantages and disadvantages. Treatment of medical conditions in which diastolic heart failure is a prominent component include pharmacotherapy with calcium channel antagonists, beta-adrenergic blocking agents, diuretic agents, and angiotensin-converting-enzyme inhibitors. Certain conditions associated with diastolic filling abnormalities such as pericardial disease or severe ischemic heart disease may be best managed by surgical or percutaneous intervention. Future research will include further delineation of the cellular mechanisms of active myocardial relaxation and clinical investigation into treatment directed at improving outcome.

Background The effects of early pressure overload on left ventricular (LV) chamber mechanics in the primate heart are poorly understood. Methods and Results To test the hypothesis that early LV pressure overload hypertrophy is associated with depression of velocity-dependent indices of LV systolic (LV dP/dt) and diastolic function (time constant of relaxation, tau) but unchanged systolic elastance (E es ), we studied six conscious baboons instrumented with LV micromanometers and LV dimension and wall thickness sonomicrometers. Loading conditions were altered by pharmacological angiotensin II generation both before and 12 weeks after producing renovascular hypertension (2 kidney, 1 clip). The LV systolic pressure (149±11 [SD] versus 114±5 mm Hg) and LV mass (125±25 versus 91±20 g) were greater 12 weeks after than before (both P es and E es normalized for LV mass were similar before versus 12 weeks after (23.0±9.6 versus 22.3±9.8 mm Hg/mL and 26.5±14.5 versus 19.8±12.5 mm Hg/mL, respectively; both P =NS). At matched LV systolic and diastolic pressures, LV fractional shortening was similar (18.6±6.8% versus 21.6±4.9%), but the time constant of LV isovolumic relaxation was significantly longer (42.3±5.3 versus 31.4±7.0 ms, P cf were significantly less (1891±352 versus 2342±284 mm Hg/s and 0.9±0.4 versus 1.1±0.3 circ/s, respectively; both P Conclusions In conscious baboons with systemic arterial hypertension and early LV hypertrophy, there is depression of velocity-dependent indices of LV contraction and relaxation but unaltered force-dependent measures of contractility.

A double-blind placebo-controlled study to determine the acute hemodynamic and cardiac mechanical effects of the quinolinone derivative OPC-18790 was performed in 12 patients with New York Heart Association class III or IV congestive heart failure. Simultaneous echocardiographic, Doppler, and invasive hemodynamic studies were performed before and after a 6-hour intravenous infusion of drug at 2.5, 5.0, or 10.0 μg/kg/min or of placebo. OPC-18790 (mean dose 5.9 ± 3.5 mg) caused significant increases in left ventricular (LV) ejection fraction (15% ± 4% vs 23% ± 5%; p < 0.05) and cardiac index (1.7 ± 0.4 vs 2.5 ± 0.6 L/min/m2; p < 0.05) and a rightward and upward shift in the stress-shortening relation. LV end-diastolic volume and heart rate were unchanged. LV filling and posterior LV wall thinning rates from digitized M-mode echocardiographic studies (0.49 ± 0.16 vs 0.75 ± 0.21 cm/sec and 2.0 ± 0.9 vs 3.0 ± 1.4 cm/sec, respectively; both p < 0.05), transmitral deceleration time (67 ± 24 vs 81 ± 19 msec, p < 0.05), and atrial filling fraction (31.0% ± 11.2% vs 38.9% ± 13.9%, p < 0.05), infusion. Despite a significant decrease in pulmonary capillary wedge pressure (28 ± 9 vs 18 ± 10 mm Hg) there was no change in the velocity-time integral of early diastolic filling (53 ± 12 vs 59 ± 22 cm), suggesting improved LV relaxation. Hemodynamics and parameters of LV function were unchanged in the 3 patients receiving placebo. We conclude that in addition to its positive inotropic effects, OPC-18790 may produce hemodynamic benefit by salutary effects on LV relaxation, atrioventricular compliance, and late ventricular diastolic filling.

Objectives. The purpose of this study was to identify the effects of altered loading conditions on left atrial appendage flow velocities. Background. Although studies have suggested that Doppler analysis of left atrial appendage blood flow may have clinical utility, the hemodynamic and cardiac mechanical determinants of left atrial appendage flow are poorly understood. Methods. Transesophageal Doppler echocardiography was performed in eight atrially paced anesthetized dogs instrumented with sonomicrometers on the left atrial appendage and the left ventricular minor axis and with left atrial and left ventricular micromanometers. Left atrial appendage emptying and filling velocities corresponding to early and late ventricular diastole, respectively, were measured using volume expansion and phenylephrine infusion. Results. Volume infusion caused a significant decrease in the early to late emptying and filling ratios (mean ± SD 0.85 ± 0.24 vs. 0.46 ± 0.17 and 0.80 ± 0.50 vs. 0.40 ± 0.20, both p < 0.05). By contrast, phenylephrine infusion did not significantly alter either filling or emptying ratio. The independent determinants of each flow wave were identified with multiple regression analysis: early emptying velocity—time constant of left ventricular relaxation, left ventricular end-systolic dimension and aortic pressure (r = 0.75, p < 0.001); late emptying velocity—left ventricular peak positive time derivative of left ventricular pressure (dPdt) and fractional shortening (r = 0.74, p < 0.001); early filling velocity—left atrial appendage shortening fraction (r = 0.45, p = 0.01) and late filling velocity—left atrial appendage lengthening rate and left ventricular fractional shortening (r = 0.56, p < 0.01). Conclusions. These results indicate that 1) both the magnitude and the pattern of left atriai appendage emptying and filling velocities are dependent on loading conditions, and 2) left atrial appendage velocities are influenced to a greater extent by changes in left ventricular than in left atrial appendage function. These findings may have implications for the pathogenesis of left atrial appendage thrombi.

Incessant supraventricular tachycardia has been demonstrated to result in a dilated cardiomyopathy in both animal models and humans. l-3 The phenomenon occurs in the absence of preexisting cardiac abnormalities. Termination of the tachycardia may lead to regression of myocardial dysfunction and normalization of left ventricular volume and systolic function. 1-4 The precise mechanisms responsible for the tachycardia-induced cardiomyopathy have not been elucidated. Hypotheses include depletion of myocardial high-energy phosphate stores, altered myocardial sarcoplasmic reticulum calcium ion transport,?, 6 abnormalities of myocardial blood flo~,~ and alterations in the myocardial capillary vasculature.8 We present a patient with an incessant supraventricular tachycardia and dilated cardiomyopathy who underwent successful radiofrequency catheter ablation of an atrioventricular nodal reentry pathway and regained normal biventricular volume and systolic function within a 3-week period. A 49-year-old woman with a history of chronic obstructive lung disease arrived at the emergency department in respiratory distress. Three weeks before presentation, the patient underwent a presurgical evaluation for an otolaryngologic procedure. At that time examination revealed an elevated pulse, and an electrocardiogram displayed a supraventricular tachycardia at a rate of 150 beats/min. The patient denied palpitations and reportedly was “asymptomatic,” so ther,apy was not initiated. Ten days later she was reevaluated by her primary care physician and, despite persistence of the tachycardia, continued to be “asymptomatic.” Several laboratory studies were ordered, and the patient was instructed to return in 2 weeks. During the interim, she had progressive dyspnea, orthopnea, and fatigue, and sought medical assistance.

Objective: The aim was to study the relation between left atrial microcirculatory flux, using laser Doppler flowmetry (LDF), and blood flow, using radiolabelled microspheres (MS). Methods: Studies were done in five anaesthetised dogs. LDF probes were sewn to the appendage and body of the left atrium. Radionuclide spheres (15 μm) were used to quantitate blood flow at baseline, and during atrial pacing at 3.5 Hz, atrial fibrillation, and intravenous adenosine infusion (1 mg·kg−1·min−1). Results: In the left atrial body, both MS and LDF perfusion increased significantly during pacing and adenosine infusion; only LDF registered significant increases during atrial fibrillation. In the left atrial appendage, MS flow failed to increase significantly with any intervention and LDF perfusion increased significantly only during atrial fibrillation. There was a significant but weak correlation (r=0.36, p

Previous studies have shown regional differences in atrial distensibility. We studied 12 open-chest dogs to test the hypothesis that left atrial compliance is decreased after removal of the left atrial appendage and to determine the effect of altered atrial compliance on atrial reservoir and conduit function. Sonomicrometer crystal pairs were used to measure the long- and short-axis diameters of the left atrium over a wide range of intracardiac pressures and volumes obtained by intravenous hetastarch infusion both before and after suture ligation of the left atrial appendage (appendectomy). Pulmonary venous flow was measured with an ultrasonic flowmeter, and transmitral flow velocities were measured with transesophageal Doppler echocardiography. After appendectomy, the diastolic pressure-volume relation was shifted upward and to the left in six of seven dogs. The mean dynamic stiffness constant of the left atrial diastolic pressure-volume relation was significantly greater after appendectomy than before (0.20 +/- 0.11 [mean +/- SD] versus 0.14 +/- 0.08 ml-1, p < 0.01); the mean y intercept was slightly, but significantly, less after appendectomy (0.6 +/- 0.3 versus 1.3 +/- 0.6 mm Hg, p < 0.05). The left atrial reservoir volume (maximum minus minimum left atrial volume) was significantly less after appendectomy at matched left atrial pressures. The systolic to diastolic flow integral ratio of pulmonary venous flow (JFTI/KFTI), an index of the relative reservoir to conduit functions of the left atrium, increased significantly with volume infusion only before appendectomy; at matched left atrial pressure, JFTI/KFTI was significantly less afterwards.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonbacterial thrombotic endocarditis is a condition characterized by noninfectious valvular vegetations and is associated with numerous conditions, including the antiphospholipid syndrome. Although vegetations most frequently affect the left-sided valves, isolated involvement of the right-sided valves rarely occurs. Ideal management of the lesions, from both medical and surgical perspectives, is not well defined. The authors report the case of a patient who presented with clinically symptomatic isolated tricuspid valve and right atrial nonbacterial thrombotic endocarditis due to primary antiphospholipid syndrome, who was subsequently managed with diuretics and anticoagulation and has remained clinically stable.

BACKGROUND Although recent studies suggest that pulmonary venous flow velocities may be used to evaluate left ventricular diastolic function, the influence of loading conditions and contractile state on the magnitude and pattern of pulmonary venous flow are poorly understood. METHODS AND RESULTS Fourteen anesthetized open-chest mongrel dogs were instrumented with pulmonary venous flow probes, atrial sonomicrometer crystal paris, and high-fidelity micromanometers; transesophageal Doppler echocardiography was used to obtain simultaneous pulmonary venous flow velocities. Measurements were made over a wide range of left atrial pressure obtained by either intravascular volume infusion and inferior vena caval balloon inflation (n = 8), halothane inhalation (n = 6), or phenylephrine infusion (n = 5). There was an excellent correlation for pulmonary venous systolic (J) to diastolic (K) time integral between the Doppler and flow probe signal (r = 0.94; SEE, 0.18). When left atrial pressure was increased by volume infusion, there was a significant linear relation between mean left atrial pressure and the Doppler J/K peak (r = 0.64; SEE, 3.4 mm Hg) and flow velocity-time integral ratio (r = 0.75; SEE, 2.9 mm Hg). By contrast, when left atrial pressure was elevated by halothane-induced cardiac depression, there was no correlation. The independent determinants of the pattern of pulmonary venous flow (stepwise multiple linear regression analysis) under all conditions were atrial systolic shortening, aortic systolic pressure, heart rate, and left ventricular end-systolic dimension (cumulative r = 0.80). CONCLUSIONS The pattern of pulmonary venous flow can be measured accurately with Doppler velocities and is differentially influenced by loading conditions and myocardial contractile state; in the absence of myocardial contractile dysfunction, the pattern of pulmonary venous flow may provide an estimate of left atrial pressure; and pulmonary venous flow is determined largely by atrial systolic function.

Background Therapeutic potential was evaluated in a rat model of myocardial infarction using nanofiber-expanded human cord blood derived hematopoietic stem cells (CD133+/CD34+) genetically modified with VEGF plus PDGF genes (VIP). Methods and Findings Myocardial function was monitored every two weeks up to six weeks after therapy. Echocardiography revealed time dependent improvement of left ventricular function evaluated by M-mode, fractional shortening, anterior wall tissue velocity, wall motion score index, strain and strain rate in animals treated with VEGF plus PDGF overexpressed stem cells (VIP) compared to nanofiber expanded cells (Exp), freshly isolated cells (FCB) or media control (Media). Improvement observed was as follows: VIP>Exp> FCB>media. Similar trend was noticed in the exercise capacity of rats on a treadmill. These findings correlated with significantly increased neovascularization in ischemic tissue and markedly reduced infarct area in animals in the VIP group. Stem cells in addition to their usual homing sites such as lung, spleen, bone marrow and liver, also migrated to sites of myocardial ischemia. The improvement of cardiac function correlated with expression of heart tissue connexin 43, a gap junctional protein, and heart tissue angiogenesis related protein molecules like VEGF, pNOS3, NOS2 and GSK3. There was no evidence of upregulation in the molecules of oncogenic potential in genetically modified or other stem cell therapy groups. Conclusion Regenerative therapy using nanofiber-expanded hematopoietic stem cells with overexpression of VEGF and PDGF has a favorable impact on the improvement of rat myocardial function accompanied by upregulation of tissue connexin 43 and pro-angiogenic molecules after infarction.

The effect of prior splenectomy on the hemodynamics of cardiac tamponade was investigated in 15 closed-chest pentobarbital sodium-anesthetized dogs. Hemodynamics were compared at baseline and during staged cardiac tamponade (pericardial pressures of 5, 10, and 15 mmHg) at control (n = 15) and after splenectomy (n = 8) and sham operation (n = 7). The fall in mean arterial pressure with cardiac tamponade was significantly greater in splenectomized dogs than in either sham-operated or control dogs (P less than 0.001). Cardiac output was more depressed at the third level of cardiac tamponade in splenectomized than in sham-operated or control dogs (12.8 +/- 14.5 vs. 29.3 +/- 8.7 and 25.4 +/- 9.4 ml.min-1.kg-1, respectively; both P less than 0.05 vs. splenectomy). Hemodynamic failure, defined as an inability to maintain mean arterial pressure greater than 50 mmHg for 5 min, occurred at a lower pericardial pressure in splenectomized than in sham-operated dogs (13.1 +/- 3.8 vs. 18.1 +/- 3.5 mmHg, P less than 0.05). Hematocrit increased significantly with cardiac tamponade in controls and sham-operated but not splenectomized dogs. The percent increase in hematocrit from baseline to the third stage of cardiac tamponade was 19.6 +/- 9.8 and 22.3 +/- 5.6% in control and sham dogs, respectively. Thus the canine spleen plays an important role in cardiovascular compensation to cardiac tamponade. Parallel changes in hematocrit suggest that a part of this response is due to splenic autotransfusion.

Despite recent reports describing survival after cardiac rupture, the effectiveness of circulatory support while awaiting definitive surgical treatment is controversial. To assess the efficacy of volume expansion and pharmacologic support in cardiac tamponade due to cardiac rupture, a model of hemorrhagic cardiac tamponade was developed and treatment with rapid saline infusion and dobutamine was compared with rapid saline infusion alone in 15 closed chest dogs. A right ventricular wound of reproducible size was produced by deflating an aortic valvuloplasty balloon that had previously been passed by way of the internal jugular vein into the pericardial space and through a stab wound in the right ventricular free wall. Hemodynamic values were compared at baseline, during tamponade and after a rapid infusion (1 liter at 100 ml/min) of either saline solution alone or saline solution plus dobutamine (20 micrograms/kg per min). Atrial and pericardial pressures increased significantly in both groups. Mean arterial pressure, cardiac output and stroke volume increased with combined saline and dobutamine infusion to values similar to those at baseline (91 +/- 19%, 114 +/- 43% and 94 +/- 37% of baseline, respectively). In contrast, saline infusion alone caused a small increase in cardiac output but failed to significantly increase mean arterial pressure or stroke volume (76.8 +/- 14.2%, 55 +/- 18% and 51 +/- 17% of baseline, respectively). Combined rapid infusion of saline solution and dobutamine infusion has a more beneficial hemodynamic effect and may be more effective than rapid saline infusion alone in resuscitating patients with hemorrhagic cardiac tamponade due to cardiac rupture.

Background Indigenous high-altitude populations have distinctive biologic characteristics that appear to be adaptive. Thus, although evidence suggests that homogeneous and genetically distinct populations in the Andean and Tibetan Highlands have adapted differentially their pulmonary hemodynamics to high-altitude stress, the situation for the third major high-altitude area, Ethiopia, is unknown. Objectives and Methods Accordingly, we examined noninvasively pulmonary arterial hemodynamics using Doppler echocardiography (MyLab30CV, Biosound Esaote, Inc.) in 193 healthy, nonsmoking, male and nonpregnant female Amharic adults, 18 to 55 years of age, from the Semien Mountain Region of NW Ethiopia native to high (3,900 m) or low (1,200 m) altitudes and 51 matched US sea-level native resident controls (240 m). Standard parasternal, apical, and subcostal two-dimensional views were obtained and color flow-directed pulsed-wave Doppler of transvalvular flows and continuous-wave Doppler of the tricuspid regurgitant flow were measured. An adequate tricuspid regurgitant jet gradient (TRgrad) was obtained in 71% of Ethiopians and in 92% of controls. The TRgrad and the velocity-time integral of right ventricular outflow (RVOTvti) were used as surrogates of pulmonary artery pressure and pulmonary blood flow, respectively, and pulmonary vascular resistance indexed to body surface area (PVRi) was calculated using a validated method using the TRgrad and the RVOTvti.Results(seeTable):High-altitude native residents had significantly higher pulmonary artery systolic pressures than low-altitude natives and sea-level controls. Moreover, compared with the sea-level controls, high-altitude natives had significantly higher pulmonary blood flow, hemoglobin (Hb) level, and arterial oxygen content and lower PVR and Hb saturation. Conclusions We conclude that (1) pulmonary artery pressure is higher in native high-altitude Ethiopians but is generally mild and offset by pulmonary vascular resistance; (2) the Ethiopian adaptation to high altitude involves increased pulmonary blood flow and arterial oxygen delivery. Funding from an NSF grant (0452326) to C.M.B. and ASE Sonographer grant to N.D.

Cardiac hypertrophy and heart failure are characterized by increased expression of atria natriuretic peptide (ANP), a decrease in the activity of fatty acid oxidation (FAO) enzymes, impaired mitochondrial respiration, and LV remodeling and systolic dysfunction. Fatty acids up-regulates the expression of FAO enzymes via activation of peroxisomal proliferator activator receptors. We hypothesized that a high-fat diet would prevent down-regulation of FAO enzymes activity and slow development of cardiac dysfunction in a model of hypertension-induced hypertrophic cardiomyopathy. Three groups ( n = 10) of 11-week-old male Dahl salt-sensitive rats were fed (1) low-fat/low-salt rodent chow (10% calories from fat) (LF-LS), (2) low-fat/high-salt chow (6% NaCl) (LF-HS), or a high-fat/high-salt diet (60% calories from fat, 6% NaCl) (HF-HS) for 12 weeks. Tail cuff blood pressure and echocardiographic assessment of LV dimensions and function were performed before initiation of diets and after 11 weeks on diets. Myocardial activities of citrate synthase (CS) and medium chain acyl dehydrogenase (MCAD) activities were measured, and the mRNA expressions for ANP was measured. Results There were no differences in body weight among groups. Salt feeding caused similar elevations in systolic blood pressure in LF-HS and HF-HS groups (

Introduction Doppler echocardiography plays a critical role in identifying valvular insufficiency that may complicate the use of phen-fen and related drugs. However, the prevalence of unsuspected, preexisting valvular regurgitation in a large, heterogeneous population is poorly defined. Methods 6,861 records were examined from consecutive individuals without known or suspected valve disease referred to the UHC echo laboratory for nonvalvular-related indications from 2001-2003. Mitral (MR) and aortic (AI) regurgitant severity was graded using a clinical composite of published 2-D, spectral, and color flow-Doppler methods. Multiple logistic analysis (SPSS, v13) was used to model clinical variables (age, gender, left ventricular ejection fraction [LVEF], body mass index [BMI], history of hypertension [HTN], LV hypertrophy [LVH], history of coronary disease [CAD]) and valvular morphology. Results Prevalence estimates for moderate or greater MR and mild or greater AI as a function of age are shown in the figure. Female gender predicted MR (OR 2.12, 95% CI 1.78-2.53), but AI was gender neutral. Regurgitant severity increased with decreasing EF and BMI, and the presence of LVH, HTN, and CAD were not predictive. Regurgitation prevalence was significantly influenced by both nonspecific and specific valve abnormalities. Conclusions The prevalence of moderate or greater MR and mild or greater AI is substantial, increases exponentially with age, and is predicted by commonly used clinical variables. These prevalence estimates should be considered when assessing the finding of unanticipated MR or AI on echocardiogram.

Expression of cardiac fatty acid oxidation (FAO) enzymes is regulated by the nuclear transcription factor peroxisome proliferator activated receptor α (PPARα). Previous studies suggest that activation of PPARα might impair left ventricular (LV) function and increased heart failure (HF) progression. We tested the hypothesis that increased FAO enzyme expression is associated with accelerated LV dysfunction and dilation in HF. Rats underwent either left coronary artery ligation to induce HF (n = 18) or sham operation (n = 9). Eight weeks after ligation, infarcted rats were assigned treatment with fenofibrate, a PPARα agonist (150 mg/kg/day; HF + FENO, n = 9) or left untreated (HF, n = 9). After 12 weeks of treatment, rats were studied with 2-D echocardiography. LV tissue was subsequently isolated and weighed, then freeze clamped for the measurement of medium chain acyl-CoA dehydrogenase (MCAD), carnitine palmitoyl transferase I (CPT-I) and pyruvate deyhydrogenase kinase 4 (PDK-4) expression by real-time RT-PCR. Results: HF resulted in a decrease in fractional shortening (FS) and an increase in end diastolic diameter (EDD) compared to sham, and there were no differences in LV function or dilation between HF and HF + FENO groups. The LV mass (both absolute and normalized for body weight) and MCAD, CPT-I and PDK-4 expression were significantly increased in HF + FENO compared to HF and sham. There were no statistically significant differences in LV mass or mRNA expression between the HF and sham groups. Conclusion: Activation of PPARα with fenofibrate increased expression of genes of FAO enzymes and triggered a hypertrophic response without adversely affecting cardiac function or LV dilation. (Table)

Familial hypertrophic cardiomyopathy (FHC) is a genotypically heterogenous disease produced by mutations in sarcomeric proteins. A missense mutation in the o~-tropomyosin gene at amino acid residue 180 (TMGIul80GIy) is a recently reported cause of FftC. Transgenic mice (TG) with mutant TM driven by the MHC promotor (4 lines, 10-40 copy number), die at 3-4 months of age, and at necropsy exhibit 3-fold cardiac enlargement, ventricular hypertrophy, and atrial fibrosis. In order to evaluate in vivo effects of TMGIuI80Gly on LV function and geometry, 2D-guided M-mode and color flow-guided Doppler were performed in 6 TG and 6 littermate controls (WT) aged 3 months. LV mass normalized to body weight (LV/BW) and the ratio of LV wall thickness to cavity (h/r) were significantly greater in TG than WT

Delayed Restitution of Contractility Reflects Impaired Calcium Handling in Pacing Induced Heart Failure in Immature Goats