Normal Right Ventricular Three‐Dimensional Architecture, as Assessed with Diffusion Tensor Magnetic Resonance Imaging, is Preserved During Experimentally Induced Right Ventricular Hypertrophy
Eva Amalie NielsenMorten SmerupPeter AggerJesper FrandsenS. RinggardMichael PedersenPeter VestergaardJens R. NyengaardJohnnie B. AndersenPaul P. LunkenheimerRobert H. AndersonVibeke E. Hjortdal
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Abstract The three‐dimensional architecture of the right ventricular myocardium is a major determinant of function, but as yet no investigator‐independent methods have been used to characterize either the normal or hypertrophied state. We aimed to assess and compare, using diffusion tensor magnetic resonance imaging, the normal architecture with the arrangement induced by chronic hypertrophy. We randomized 20 female 5 kg piglets into pulmonary trunk banding (N = 16) and sham operation (N = 4). Right ventricular hypertrophy was assessed after 8 weeks. The excised and fixed hearts were subject to diffusion tensor imaging to determine myocyte helical angles, and the presence of any reproducible tracks formed by the aggregated myocytes. All banding animals developed significant right ventricular hypertrophy, albeit that no difference was observed in terms of helical angles or myocardial pathways between the banded animals and sham group animals. Helical angles varied from ∼70 degrees endocardially to −50 degrees epicardially. Very few tracks were circular, with helical angles approximating zero. Reproducible patterns of chains of aggregated myocytes were observed in all hearts, regardless of group. The architecture of the myocytes aggregated in the walls of the right ventricle is comparable to that found in the left ventricle in terms of endocardial and epicardial helical angles, however the right ventricle both in the normal and the hypertrophied state lacks the extensive zone of circular myocytes seen in the mid‐portion of the left ventricular walls. Without such beneficial architectural remodelling, the porcine right ventricle seems unsuited structurally to sustain a permanent increase in afterload. Anat Rec, 2009. © 2009 Wiley‐Liss, Inc.Keywords:
Afterload
Right ventricular hypertrophy
The effect of nitroglycerin (NTG) is mainly a reduction in preload and afterload. The decrease in afterload may be caused by a fall of total systemic resistance (TSR) or by an increase of arterial compliance (AC). The effects of NTG on TSR and AC were tested in 10 patients given 1.6 mg NTG sublingually. The capacity of the whole Windkessel (C) was calculated as C=τ/TSR (τ = time constant of the diastolic aortic pressure decay). The diameter of the descending thoracic aorta was measured from an aortogram. Aortic stiffness SAO) was calculated SAO = ΔP/ΔD. Since mean aortic pressure decreased by 6% after NTG without any change in cardiac index or heart rate, there had to be a primary reduction of afterload as measured from mean systolic resistance (−9%). This reduction of afterload could not be related to a decrease in TSR and SAO, C, however increased by an average of 27%. These data indicate that NTG decreases the muscular tone of postaortic muscular vessels and, hence, increases the Windkessel capacity, while aortic compliance does not change.
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One of the most controversial problem in cardiac muscle pathology is the existence of myocyte hyperplasia. The term hypertrophy indicates an increase in size of the individual muscle cells without changing their total number, whereas in hyperplasia there occurs proliferation of the myocyte. This fundamental question of the character of cardiac growth remains unresolved in spite of the wide attention it has received. Contemporary views concerning the cardiac muscle hyperplasia are presented. From clinical point of view the problem is significant for two reasons. The loss of the ability of muscle cells to proliferate is responsible for the irreversible myocardial destruction after injury. From another point of view, if the increase of the heart muscle is maintained, although a complete remission of cardiac hypertrophy becomes impossible. In 103 hearts with various forms of cardiac muscle hypertrophy the following parameters were estimated: diameter, length, volume, density and number of myocytes, as well as the density of nuclei of myocytes. The values of all histometric parameters correlated well with the LV weight up to 350 g. In heavier hearts these parameters were approximately at the same magnitude. The number of myocytes was significantly higher in hearts with LV weight above 250 g than in hearts below 250 g: 5.53 x 10(9) vs 4.31 x 10(9), p < 0.001. The influence of coronary artery diameters, degree of atherosclerosis, weight and percent of fibrous tissue and age on LV weight were evaluated as well. From these parameters only coronary artery diameters significantly influenced on LV weight.(ABSTRACT TRUNCATED AT 250 WORDS)
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Rational use of vasodilators to induce afterload reduction is predicated on a thorough knowledge of the constituents of afterload and of the role ventriculoarterial coupling plays in determining their effects. Afterload reduction therapy should be goal directed with the intent to improve stroke volume and tissue oxygen delivery rather than to decrease blood pressure per se. This review will summarize the components comprising circulatory system afterload and will use ventriculoarterial coupling concepts to demonstrate the variable but predictable effects of vasodilator therapy on hemodynamics and tissue oxygen delivery. This article addresses the third of eight topics comprising the special issue entitled "Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery".
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Afterload plays important roles during heart development and disease progression, however, studying these effects in a laboratory setting is challenging. Current techniques lack the ability to precisely and reversibly alter afterload over time. Here, we describe a magnetics-based approach for achieving this control and present results from experiments in which this device was employed to sequentially increase afterload applied to rat engineered heart tissues (rEHTs) over a 7-day period. The contractile properties of rEHTs grown on control posts marginally increased over the observation period. The average post deflection, fractional shortening, and twitch velocities measured for afterload-affected tissues initially followed this same trend, but fell below control tissue values at high magnitudes of afterload. However, the average force, force production rate, and force relaxation rate for these rEHTs were consistently up to 3-fold higher than in control tissues. Transcript levels of hypertrophic or fibrotic markers and cell size remained unaffected by afterload, suggesting that the increased force output was not accompanied by pathological remodeling. Accordingly, the increased force output was fully reversed to control levels during a stepwise decrease in afterload over 4 hours. Afterload application did not affect systolic or diastolic tissue lengths, indicating that the afterload system was likely not a source of changes in preload strain. In summary, the afterload system developed herein is capable of fine-tuning EHT afterload while simultaneously allowing optical force measurements. Using this system, we found that small daily alterations in afterload can enhance the contractile properties of rEHTs, while larger increases can have temporary undesirable effects. Overall, these findings demonstrate the significant role that afterload plays in cardiac force regulation. Future studies with this system may allow for novel insights into the mechanisms that underlie afterload-induced adaptations in cardiac force development.
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Male Wistar rats were exposed, in a hypobaric chamber, to a simulated altitude of 6000 m for up to four weeks. The animals quickly developed pulmonary hypertension with an important media hypertrophy of the pulmonary arteries, followed by severe right heart hypertrophy (cor pulmonale). Right heart hypertrophy is evident in three morphologically and biochemically definable stages. In stage 1 (1st-2nd week) a manifest thickening of heart muscle cells develops due to increased protein synthesis. In stage 2 (2nd-3rd week) one can find, in the regular biochemical composition of heart muscle, an activation of mitochondrial ATPase, a multiplication of mitochondria, a proliferation of interstitial cells and an increase in interstitial volume. In stage 3 (3rd-4th week) the hypertrophied myocardium exhibits signs of biochemical and morphological decompensation. Besides a loss of myofibrils and a reduction in mitochondrial ATPase, DNA and protein concentrations sink to subnormal values. Only myocardium from stage 1 of hypertrophy shows complete reversibility after cessation of hypobaric conditions, but not so in stage 3. Parallel with the developing cor pulmonale, the animals also react with a small hypertrophy of the left heart ventricle. This concomitant growth persists under normobaric conditions, too. These investigations document that growth of myocardium under extreme conditions shows a phasic development. Severe forms of myocardial hypertrophy do not always seem to be reversible.
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The concept of a maximum tolerable afterload and an afterload reserve was proposed for evaluating ventricular function. A maximum tolerable afterload was defined as the systolic ventricular pressure during gradual proximal arterial obstruction, at the point where a distal arterial pressure or flow began to fall. An afterload reserve was defined as the difference between a maximum tolerable afterload and a basal afterload. By using right heart bypass preparations in dogs, a maximum tolerable afterload and an afterload reserve were compared with the ventricular function curve. An improved ventricular function curve was always associated with a greater maximum tolerable afterload and a greater afterload reserve, whereas a depressed function curve with a smaller maximum tolerable afterload and a smaller afterload reserve.
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Right ventricular (RV) failure induced by sustained pressure overload is a major contributor to morbidity and mortality in several cardiopulmonary disorders. Reliable and reproducible animal models of RV failure are therefore warranted in order to investigate disease mechanisms and effects of potential therapeutic strategies. Banding of the pulmonary trunk is a common method to induce isolated RV hypertrophy but in general, previously described models have not succeeded in creating a stable model of RV hypertrophy and failure. We present a rat model of pressure overload induced RV hypertrophy caused by pulmonary trunk banding (PTB) that enables different phenotypes of RV hypertrophy with and without RV failure. We use a modified ligating clip applier to compress a titanium clip around the pulmonary trunk to a pre-set inner diameter. We use different clip diameters to induce different stages of disease progression from mild RV hypertrophy to decompensated RV failure. RV hypertrophy develops consistently in rats subjected to the PTB procedure and depending on the diameter of the applied banding clip, we can accurately reproduce different disease severities ranging from compensated hypertrophy to severe decompensated RV failure with extra-cardiac manifestations. The presented PTB model is a valid and robust model of pressure overload induced RV hypertrophy and failure that has several advantages to other banding models including high reproducibility and the possibility of inducing severe and decompensated RV failure.
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To evaluate the effects of afterload on peak rate of tension rise (dT/dt) in the isolated muscle.Left ventricular papillary muscles from Wistar rats were studied in isometric and isotonic afterloaded contractions. Muscles were analised in Krebs-Henseleit solution with calcium concentration of 2.52mM at 28 degrees C. The resting muscle length (preload) was maintained constant. The peak isometric developed tension (DT) and dT/dt were measured during increases of afterload (25, 50, 75 and 100% from DT).A rise in afterload corresponding to 50, 75 and 100% of DT, did not cause an increase in dT/dt values (p > 0.05). The dT/dt value decreased (p < 0.05) when afterload was changed from 75% to 25% of DT.The data suggest that an increase in the afterload from 50% of the DT did not promote changes in the dT/dt.
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