Normal Human Ventricle Research Articles

Sex-related differences in age-associated downregulation of human ventricular myocardial β1-adrenergic receptors

With increasing age, human ventricular myocardium exhibits selective downregulation of β1-adrenergic receptors (β1-ARs). We tested the hypothesis that sex differences exist in age-related changes in β1-ARs. Left (LV) and right (RV) ventricular tissue was obtained from 61 unplaceable potential organ donor hearts ages 1 to 71 years with no known cardiac history and from LVs removed from 56 transplant recipients with idiopathic dilated cardiomyopathy. β1-AR and β2-AR densities, the frequency of β1-AR389 gene variants, and β-AR function were determined. Sex had a marked effect on the age-related decrease in β1-ARs. Female LVs had more pronounced downregulation (by 42% [p < 0.001] vs 22% [p = 0.21] in 31 male LVs) comparing the youngest (average age, 15.3 ± 5.5 years) to the oldest (average age, 50.8 ± 9.1 years) sub-groups. On regression analyses, female LVs exhibited a closer relationship between β1-AR density and age (r = -0.78, p <0.001 vs r = -0.46, p = 0.009 in males), with a second-degree polynomial yielding the best fit. There was no statistically significant relationship of β1-ARs to age in female or male idiopathic dilated cardiomyopathy LVs. Sex affects age-related β-AR downregulation in normal human ventricles, with females exhibiting more profound decreases with increasing age. The curvilinear relationship between age and receptor density that plateaus around age 40 in women suggests an effect of sex hormones on β1-AR expression in the human heart.

Differential Twitch Kinetics in Engineered Cardiac Tissue Expressing Human Cardiac Myosins

Congestive heart failure is a debilitating disease in which the principal pathology is impaired ventricular contractility leading to diminished cardiac output, and previous work indicates that reduced contractility is based in part on the ratio of myosin heavy chain (MyHC) isoforms, α- and β-MyHC, expressed in the ventricles. Normal human ventricles express ∼10% of the fast α-MyHC on a background of the slower β-MyHC, while in failing hearts α-MyHC is reduced to virtually undetectable levels with complete replacement by β-MyHC. Data from permeabilized myocardial preparations suggests that this isoform switch may be partly responsible for reduced myocardial twitch force and pressure development by failing ventricles since β-MyHC is a slower motor protein, yet most experiments have used non-human myosins and experimental conditions in which preparations were steadily activated, thus little is known about the response of human myosins to a time-varying Ca2+ transient. To address these limitations, we recently developed a human 3D engineered cardiac tissue (hECT) system in which we can express recombinant human muscle myosin motors. Using commercially available cloning and adenoviral expression systems, α- or β-MyHC isoform expressing adenoviral particles were used to transduce human cardiomyocytes produced from human iPS cells and construct hECTs. Preparations displayed well-defined cellular structure with elongated morphology aligned in the direction of preparation shortening during electrical pacing, while histological analysis of hECT revealed appropriate protein expression and localization within the sarcomere. In response to a Ca2+ transient, the time-course of twitch force development was accelerated in hECT expressing α-MyHC compared to β-MyHC, while peak twitch force was greater in hECT expressing α-MyHC. These results demonstrate the relative contribution of myosin isoforms to myocardial twitch kinetics in human engineered cardiac tissue constructs expressing a stable background of myofibrillar proteins.

A three-dimensional computational investigation of intraventricular fluid dynamics: examination into the initiation of systolic anterior motion of the mitral valve leaflets.

Systolic anterior motion of the mitral valve leaflets (SAM) is a disease of the left ventricle which results from an abnormal force balance on the mitral valve. The mechanism by which is initiated is poorly understood, and a complete understanding of this mechanism is required for effective treatment of SAM. There are currently two theories for the initiation mechanism of SAM, the Venturi hypothesis and the altered papillary muscle-mitral valve geometry theory (PM-MV). The Venturi hypothesis states that abnormally high ejection velocities create Venturi forces which initiate SAM. The PM-MV theory asserts that SAM is the result of abnormally distributed chordal forces which are incapable of preventing SAM. To investigate the initiation mechanism of SAM, a computer model of early systolic flow in an anatomically-correct human left ventricle was developed using Peskin's immersed boundary algorithm. The computer model was used to determine the effect of chordal force distribution and septal thickness of the intraventricular flow field. The results show that the degree of SAM is inversely proportional to the amount of chordal restraint applied to the central portion of the leaflets. Also, the results support the PM-MV theory and indicate the following: (i) fluid forces capable of initiating SAM as always present in a normal human ventricle; (ii) SAM does not occur normally because of the presence of chordal forces on the central portion of the mitral leaflet; (iii) SAM will occur when these central chordal forces are sufficiently low; (iv) the extent of SAM is inversely proportional to these central chordal forces; and (v) Venturi forces alone can not cause SAM.

Detection of enterovirus RNA in myocardial biopsies from patients with myocarditis and cardiomyopathy using gene amplification by polymerase chain reaction.

Recent molecular studies have suggested that viral myocarditis frequently underlies human congestive cardiomyopathy; however, only moderately sensitive and specific techniques were used. Polymerase chain reaction (PCR) gene amplification is a sensitive, specific technique ideally suited for the diagnosis of viral disease in small tissue samples where low copy numbers of the viral genome may be present. Using PCR and high stringency condition, we screened biopsies taken from 48 patients with clinically suspected myocarditis or dilated cardiomyopathy. Five patients demonstrated positive enteroviral signals by PCR; two of them had myocarditis by pathology, whereas the other three had changes consistent with cardiomyopathy. Four other patients had myocarditis diagnosed by pathology from 3 months to 1 year earlier but were now negative by both PCR and pathology. Both pathology and PCR were negative for active myocarditis in all other patients. Ventricular samples taken from left ventricular myectomy in four additional patients with hypertrophic cardiomyopathy, normal human ventricle samples, and uninfected monkey kidney cells were also negative by PCR. This study supports a link between viral infection and dilated cardiomyopathy in some patients. PCR gene amplification provides a new diagnostic approach to patients with suspected myocarditis.

Distribution pattern of alpha and beta myosin in normal and diseased human ventricular myocardium.

All fibers in three normal, four dilated, and two ischemic human ventricles were classified according to their myosin content using three sets of monoclonal antibodies each specific for one myosin heavy chain isoform (alpha, beta and beta'). Numerous fibers contained only beta myosin heavy chain (denoted as beta fibers), others contained either alpha and beta, or beta and beta' myosin heavy chain (denoted as alpha beta and beta beta' fibers, respectively). The percentages of alpha beta fibers were systematically determined along the walls of seven homologous regions of the ventricular myocardium. In all ventricles, there was an alpha beta-fiber transmural gradient, with less alpha beta fiber in the subendocardium than in the subepicardium. More alpha beta fibers were found in the right than in the left ventricular wall but there was no difference between the mid-portion and the apex of the free wall of each ventricle. The diseased ventricles contained a lower alpha beta fiber percentage than the normal hearts. beta beta' fibers were very rare in the normal ventricles (less than 5%) and almost inexistent in pathological hearts. The correlation between the mean alpha beta fiber percentages of the diseased hearts and their cardiac indices (r = 0.88, P less than 0.05) suggests that the small amount of alpha myosin distributed in a large number of ventricular fibers could play a role in the contractile performance of the heart. In conclusion, this study provides evidence for 1) an alpha beta fiber transmural gradient, and 2) a lower alpha myosin ratio in diseased than in normal human ventricle.

Isozymic changes in myosin of human atrial myocardium induced by overload. Immunohistochemical study using monoclonal antibodies.

An immunohistochemical study using monoclonal antibodies specific for the heavy chains of either human atrial (HC alpha) or ventricular (HC beta) myosin was performed to clarify the distribution of each isozyme in normal as well as pressure-overloaded human hearts. In normal human ventricles, all muscle fibers were stained by a monoclonal antibody (HMC14) specific for HC beta, whereas a small number of fibers reacted with a monoclonal antibody (CMA19) specific for HC alpha. In contrast, in normal human atria, almost all muscle fibers were stained by CMA19, and a relatively larger number of muscle fibers also reacted with HMC14. Furthermore, in pressure-overloaded atria, muscle fibers reactive with HMC14 were strikingly increased while those reactive with CMA19 showed a corresponding decrease. The extent of this isozymic redistribution was in good correlation with atrial pressure. These results not only confirmed the existence of isoforms of myosin heavy chain in human hearts, but also demonstrated that redistribution of iso-myosins could occur as an adaptation to pressure overload.

Normal left ventricular function.

The Starling relationship in the normal human ventricle may be different than usually portrayed. In normal, resting, supine man the ventricular function curve is at its peak at a left ventricular end-diastolic pressure of approximately 10 mm Hg. Below this point is a strong direct relation between filling pressure and stroke work, while at higher filling pressures, a plateau occurs. Limitation of ventricular response is related to a sharply rising ventricular pressure-volume curve at a normal level of filling pressure. Thus, in the supine position, the normal heart is not on the active portion of the ventricular function curve, but is in a unique position in which cardiac output is probably controlled by factors other than ventricular filling pressure. In ventricular failure, the peak of the ventricular function curve is displaced to a higher level.

Effect of mexiletine on conduction of premature ventricular beats in man: a study using monophasic action potential recordings from the right ventricle.

Ventricular conduction intervals between a stimulating pacemaker electrode at the right ventricular apex and an impulse detecting monophasic action potential electrode at the right ventricular septum were measured in nine subjects. The right ventricle was paced at a constant rate and programmed premature ventricular stimuli were introduced after every eighth paced beat beginning at the refractory period. The ventricular conduction intervals were measured from the pacemaker artefact to the onset of depolarisation of the MAP recording. In the control recordings a short period of prolonged (subnormal) conduction lasting for 5 to 26 ms after the refractory period was present in six of the nine subjects. In eight subjects a period of 'supernormal' conduction lasting from 50 to 180 ms was present. The effect of mexiletine was to increase the subnormal conduction and to abolish the supernormal conduction. It is concluded that a small degree of supernormal conduction occurs in the normal human ventricle possibly as a result of phase 4 depolarisation of cells of the specialised conducting system.

Echocardiographic Approach for the Clinical Assessment of Left Ventricular Function : The analysis of end-systolic pressure (wall stress)-diameter relation and force-velocity relation of ejecting ventricle. : SYMPOSIUM ON CURRENT TOPICS AND FUTURE PROSPECTS IN ECHOCARDIOGRAPHY

Echocardiography combined with simultaneous measurement of peak systemic pressure was applied for analysis of left ventricular function within a two-dimensional framework which took into account the preload, the afterload and the level of myocardial inotropic state. This approach is particulary useful for understanding the behavior of the normal and diseased ventricle under various abnormal loading conditions where a single measurement of ejection characteristics does not necessarily reflect inotropic state. The pressure (or wall stress) - diameter loops were constructed during systolic pressure change and diameter at the end of ejection was linearly related to systolic pressure or systolic wall stress. This relation generally approximates the isovolumic length- tension relation which is independent of initial length and unique to a given level of inotropic state. The echocardiographically determined shortening velocity of the ventricular wall (mean Vcf) is inversely related to the level of afterload, if the preload is fixed. However, the normal human ventricle exhibits only minor changes in Vcf in response to a moderate acute pressure stress, as modified by the preload (Frank-Starling) reserve. If the limit of preload reserve is reached, Vcf will diminish ; that is, a mismatch between afterload and the level of inotropic state occurs. The echocardiographic approach for the assessment of cardiac performance thus allows an early detection of impairment of ventricular function and offers a possible explanation of how the ventricle operates on a descending limb of function and of how the ventricle adapts to chronic mechanical overload.

Antagonism of the contractile effect of digitalis by EDTA in the normal human ventricle

1. 1. The administration of deslanoside to normal subjects is associated with a highly significant shortening of the ejection time index. 2. 2. The reduction in serum ionizable calcium induced by the administration of Na 2 EDTA to digitalized subjects is attended by a prompt and consistent reversal of the digitalis-induced shortening of the ejection time index. 3. 3. The administration of Na 2 EDTA in undigitalized subjects evoked significantly less prolongation of the ejection time index than in digitalized individuals, although the changes in serum calcium were identical. 4. 4. It is postulated that a reduction in ionizable serum calcium antagonizes the contractile effects of deslanoside, as reflected by these alterations in the ejection time index.