Computer modeling of the effects of aortic valve stenosis and arterial system afterload on left ventricular hypertrophy

The degree of left ventricular hypertrophy is generally thought to reflect the severity of aortic stenosis. However, the compounded influence of arterial system load is poorly understood. We developed a computer model to investigate the effects of aortic valve stenosis in combination with various systemic arterial parameters in the development of left ventricular hypertrophy. Data show that an increased peripheral resistance and/or aortic valve resistance, results in an increase in left ventricular wall thickness and mass, while peak systolic wall stress remains constant. Changing arterial compliance to above normal level would not induce significant changes in wall thickness, while reduction in arterial compliance below normal would cause an increase in ventricular wall thickness. When a double load is imposed on the left ventricle by way of a stenotic valve and an increased arterial afterload, a greater and an aggregated increase in wall thickness results, hastening the hypertrophic process.     

Short-term effects of electrically induced tachycardia on antioxidant defenses in the normal and hypertrophied rat left ventricle

Increased oxidative stress resulting from enhanced production of reactive oxygen species and/or inadequate mechanisms of antioxidant defenses has been recognized as an important factor contributing to the initiation and progression of cardiac dysfunction under a wide variety of pathophysiological conditions. The main objective of this study was to examine the effect of electrically induced tachycardia on oxidative stress and the capacity of antioxidant defenses in the normal and hypertrophied left ventricle (LV) in the rat. Left ventricular hypertrophy (LVH) was produced by banding the descending abdominal aorta. The activities of antioxidant enzymes, concentrations of non-enzymatic antioxidants, and biomarkers of oxidative stress were measured in the LV of aortic-banded animals (LVH), untreated or banded rats subjected to short-term (45 min) atrial pacing [(CTR + S) and (LVH + S), respectively], and untreated (CTR) or sham-operated (SHAM) controls. The results indicate that the increase in heart rate in vivo as a result of atrial pacing to a maximum level, independent of sympathetic nerve activity, leads to a substantial increase in oxidative stress and a marked decline in the activities of antioxidant enzymes in both the normal and hypertrophied left ventricle of the rat. The accompanying increase in tissue content of α- and γ-tocopherols seem to contribute to attenuation of the oxidant stress-related loss of thiol stores in the LV. Stable left ventricular hypertrophy induced by aortic banding for six weeks has a minor impact on the capacity of the endogenous antioxidant defense system in the LV, but significantly and negatively affects the ability of the heart LV to tolerate the stress of tachycardia.     

Importance of muscle light microscopic mitochondrial subsarcolemmal aggregates in the diagnosis of respiratory chain deficiency

The purpose of this study was to evaluate relationships between subsarcolemmal mitochondrial aggregates and electron transport chain deficiencies in skeletal muscle with the objective of establishing an association between mitochondrial accumulation and electron transport chain complex deficiency. We conducted a large-scale, retrospective study to evaluate factors associated with subsarcolemmal mitochondrial aggregates (percent) in pediatric patients who received muscle biopsies for suspected respiratory chain disorders. Patients were included if they had histochemical stains for assessment of mitochondrial pathology and had biochemical testing for muscle electron transport chain complex activities. Significant positive bivariate correlations (n = 337) were found between subsarcolemmal mitochondrial aggregate percentage and electron transport chain complexes II, IV, I + III, and II + III activities. Evaluation showed that a cutoff value of > 2% subsarcolemmal mitochondrial aggregates had poor overall diagnostic accuracy (mean, 32%), compared with a < 5% cutoff (mean, 60%). To better evaluate the effects of subsarcolemmal mitochondrial aggregates percentages, patients were stratified according to lower one-third (group 1, n = 120 plus ties) and upper one-third (group 2, n = 115 plus ties) of subsarcolemmal mitochondrial aggregates values. Although only minor clinical and pathologic differences were observed, group 1 participants had significantly lower electron transport chain complex activities than group 2 for all enzymes except complex III. Logistic regression showed over 2-fold greater odds of deficiency for electron transport chain complexes I + III (P = .01) and II + III (P = .03) for group 1 participants compared with group 2. We conclude that, contrary to the previous > 2.0% subsarcolemmal mitochondrial aggregates cutoff for respiratory chain disorder, patients with a low subsarcolemmal mitochondrial aggregates percentage (≤4%) are significantly more likely to have electron transport chain complex deficiency than patients with increased subsarcolemmal mitochondrial aggregates percentage (≥10%). This morphological approach for assessment of mitochondrial proliferation may assist clinicians to select further testing to rule out an electron transport chain complex deficiency in children by other methods, including direct biochemical testing of electron transport chain complex activities, measurement of muscle coenzyme Q10 content, or evaluation for a mitochondrial DNA depletion syndrome.     

Analog simulation of two clinical conditions: (1) acute left ventricle failure; (2) exercise in patient with aortic stenosis

A computer analysis of an equivalent electronic circuit is developed. Thus it is possible to simulate the human cardiovascular system, its negative feedback loops (including the control of venous tone, of myocardial contractility, and of heart rate) and negative intrathoracic pressure. If the simulated cardiovascular system is acted upon by various disturbances their consequences can be studied in detail. The consequences of two disturbances are studied by simulation: (i) acute left ventricular failure and (ii) exercise (decreased peripheral resistance) in aortic stenosis. However, prior to the simulation of the latter, a relatively complex condition, two additional procedures are implemented, i.e. simulations of (iii) increased sympathetic tone and of (iv) aortic stenosis are performed. Simulation of exercise (decreased peripheral resistance) in aortic stenosis is also compared with data observed in patients. Results show that, by using the present equivalent circuit, conditions described above can be qualitatively and to some extent quantitatively well simulated.     

Electro- and echocardiographic study of the left ventricle in man after training

Summary Fourteen sedentary middle-aged men underwent a chest X-ray, a 12 lead ECG, a VCG, and an echocardiographic examination prior to and following 5 months of training at moderately severe intensity, on a cycle ergometer. No modification in the X-ray cardiac profile was observed following training. Some electrocardiographic (R wave amplitude in V5 and V6 and Sokolow index: SV1+RV5 or V6) and vectorcardiographic (maximal QRS vector amplitude, maximal spatial QRS vector, and R wave amplitude) indices of left ventricular hypertrophy were slightly but significantly increased following training. The echocardiographic measurements in diastole (septal and posterior wall thickness, left ventricular internal diameter, and left ventricular mass) were unchanged after training. Results suggest that electrical changes may not provide adequate indications of left ventricular morphological modifications.The lack of echocardiographic evidences of left ventricular hypertrophy suggests that: (1) training does not necessarily induce left ventricular hypertrophy; (2) the large heart sometimes observed in athletes may be the result of a genetic factor or of a prolonged and very intensive training pursued since a very young age, over a number of years; and (3) left ventricular enlargement probably plays a minor role in the increase in aerobic capacity following training.This study was supported by a grant from the Haut-Commisariat à la jeunesse, aux loisirs et aux sports, Gouvernement du Québec     

Experimental analysis of fluid mechanical energy losses in aortic valve stenosis: Importance of pressure recovery

Current methods for assessing the severity of aortic stenosis depend primarily on measures of maximum systolic pressure drop at the aortic valve orifice and related calculations such as valve area. It is becoming increasingly obvious, however, that the impact of the obstruction on the left ventricle is equally important in assessing its severity and could potentially be influenced by geometric factors of the valve, causing variable degrees of downstream pressure recovery. The goal of this study was to develop a method for measuring fluid mechanical energy losses in aortic stenosis that could then be directly related to the hemodynamic load placed on the left ventricle. A control volume form of conservation of energy was theoretically analyzed and modified for application to aortic valve stenosis measurements.In vitro physiological pulsatile flow experiments were conducted with different types of aortic stenosis models, including a venturi meter, a nozzle, and 21-mm Medtronic-Hall tilting disc and St. Jude bileaflet mechanical valves. The energy loss created by each model was measured for a wide range of experimental conditions, simulating physiological variation. In all cases, there was more energy lost for the nozzle (mean=0.27 J) than for any other model for a given stroke volume. The two prosthetic valves generated approximately the same energy losses (mean=0.18 J), which were not statistically different, whereas the venturi meter had the lowest energy loss for all conditions (mean=0.037 J). Energy loss correlated poorly with orifice pressure drop (r ²=0.34) but correlated well with recovered pressure drop (r ²=0.94). However, when the valves were considered separately, orifice and recovered pressure drop were both strongly correlated with energy loss (r ²=0.99, 0.96). The results show that recovered pressure drop, not orfice pressure drop, is directly related to the energy loss that determines pump work and therefore is a more accurate measure of the hemodynamic significance of aortic stenosis.     

细胞外信号调节激酶1/2在压力负荷诱导小鼠肥厚心肌和心衰中的表达变化及作用

目的:观察细胞外信号调节激酶1/2(ERK1/2)在小鼠主动脉弓缩窄压力超负荷诱导的肥厚心肌组织中不同时点的表达变化,探讨肥厚心肌从代偿到失代偿心力衰竭发生中的分子机制。方法:12周龄C57/BL小鼠通过主动脉弓缩窄(TAC)建立心肌肥厚模型,在1、4、8、12、16周时进行高频心脏超声、血流动力学、组织重量及心肌病理学检测,RT-PCR半定量测定心房利钠肽(ANP)、α-肌球蛋白重链(α-MHC)、bcl-2、bax mRNA,Western blotting方法检测磷酸化ERK1/2蛋白表达的变化。同时建立假手术模型,在不同时点给予相同检测后处死。结果:(1)与假手术组比较,缩窄组左室收缩期、舒张期前壁、后壁厚度、左心室收缩末期、舒张末期内径于术后呈逐渐增加趋势;左心室射血分数于术后12周显著降低(P0.05)。左室收缩压及左室压力上升和下降最大速率于术后4周明显增加,8-12周保持稳定,16周明显下降;左室舒张末压于术后8周持续增加(均P0.05)。显示心肌由左室肥厚最终发展为心力衰竭。(2)组织形态学天狼猩红染色测量心肌胶原含量及TUNEL染色测定凋亡指数显示从4周到16周呈增加趋势。(3)与假手术组比较,缩窄组心肌组织ANP术后1周至16周表达呈持续性增加;而α-MHC、bcl-2 mRNA表达呈持续性降低;bcl-2/bax比值下降;缩窄组心肌组织磷酸化ERK1/2蛋白水平术后1周明显增加,4周时达高峰,12周至16周下降至稳定(均P0.05),总ERK1/2蛋白水平无明显变化。结论:主动脉弓缩窄诱导的压力超负荷可导致左室心肌早期代偿性向心性肥厚向晚期心力衰竭发展。ERK1/2信号转导途径参与压力负荷诱导心肌肥厚和心衰的发生发展过程,并可能通过调控心肌细胞凋亡实现保护作用。     

A possible relation between pressure loading and thickened leaflets of the aortic valve: a model simulation

A much smaller percentage of thickened leaflets of the aortic valve have been found in the right or left coronary leaflet than in the noncoronary leaflet. This study investigated the pressure loading transferring to the leaflets of the aortic valve and their effects on the valvular thickening. A simple ascending aorta model was established, and a simulation was made. The pressure loading in the coronary and noncoronary leaflets then were estimated. The simulation results showed that 5.8% to 17.% percentage of pressure loading to the coronary leaflet may be decreased by the coronary perfusion in diastole. The coronary arteries play an important role on pressures in the sinuses of Valsalva. The smaller pressure loading transferring to the coronary leaflet than that to the noncoronary leaflet is one reasonable explanation related to the thickened leaflets of the aortic valve.     

Deoxyguanosine kinase mutations and combined deficiencies of the mitochondrial respiratory chain in patients with hepatic involvement

The activity of deoxyguanosine kinase (DGUOK), a mitochondrial enzyme involved in the anabolism of mitochondrial (mt) deoxyribonucleotides, governs the maintenance of the mtDNA. Deleterious mutations of the DGUOK gene are thus associated with mtDNA depletion and result in combined deficiencies of mtDNA-encoded respiratory chain enzymes. With the aim to estimate the prevalence of DGUOK mutations in a cohort of 30 patients with hepatocerebral disease and combined respiratory chain deficiencies, we studied the DGUOK gene and identified previously unreported mutations in five families. Two patients and their affected sibs, born to non-consanguineous parents, were homozygous for a missense mutation (M1T, and L250S, respectively). One patient presented a homozygous 4 pb insertion (796 insTGAT) and two other patients, and their affected sibs, were compound heterozygous (E165V/L266R and E211G/L266R, respectively). These findings allowed us to propose prenatal diagnosis in two families. In conclusion, we observed a high prevalence of DGUOK mutations (17%) in patients with hepatic involvement and combined respiratory chain deficiencies with hepatic involvement.     

内皮素-1水平与单纯行主动脉瓣置换术患者术后新发房颤的相关性分析

目的探讨内皮素-1水平与单纯行主动脉瓣置换术患者术后新发房颤的关系。 方法回顾性分析2017年6月至2019年6月于首都医科大学附属北京安贞医院结构性心脏病外科中心单纯行主动脉瓣置换术的119例患者的临床资料,根据患者术后是否新发房颤分为术后房颤组(n＝28)和无术后房颤组(n＝91)。2组患者均于全身麻醉成功后取仰卧位,常规消毒铺巾,作胸部正中切口并劈开胸骨。切开心包并悬吊,肝素化后升主动脉、右心房二阶梯引流管插管建立体外循环,转机、降温,阻断循环,切开主动脉,探查主动脉瓣病变情况,剪除病变主动脉瓣,选择合适大小的人工主动脉瓣(机械瓣或生物瓣)进行置换,全周间断缝合。关闭主动脉切口。复温、排气,开放循环。并行稳定后停止体外循环,拔出动静脉管路。常规止血关胸,结束手术。统计患者术前各项资料中最可能影响术后房颤发生的因素[性别、年龄、体重指数、内皮素-1水平、基础疾病、美国纽约心脏病协会(NYHA)心功能分级、超声心动图指标]、术中资料(术中体外循环时间、主动脉阻断时间)及术后资料[术后机械通气时间、术后住院时间、行开胸止血术例数、使用何种类型人工瓣膜(机械瓣或生物瓣)]。数据比较采用t检验、非参数检验、χ²检验;通过受试者工作特征(ROC)曲线确定内皮素-1预测术后新发房颤的截断值;采用单因素和多因素Logistic回归分析与术后新发房颤相关的危险因素。 结果(1)术后房颤组患者的年龄为(53.0±12.1)岁,高于无术后房颤组[(47.1±13.6)岁],术前内皮素-1水平为0.43±0.19,高于无术后房颤组(0.27±0.14),NYHA分级≥3级患者比例为14.3%(4/28),高于无术后房颤组[4.4%(4/91)],左心房直径为(40.6±4.8) mm,大于无术后房颤组[(36.7±5.2 ) mm],主动脉瓣狭窄患者比例为39.3%(11/28),低于无术后房颤组[60.4%(55/91)],2组比较差异均有统计学意义(P<0.05);其他术前资料比较差异均无统计学意义(P>0.05)。(2)术后房颤组患者术中体外循环时间为(113.9±41.7) min,主动脉阻断时间为(75.3±24.1) min,无术后房颤组患者术中体外循环时间为(108.6±46.3) min,主动脉阻断时间为(72.5±31.4) min,2组比较差异均无统计学意义(t＝－0.547、－0.432,P＝0.59、0.67)。(3)术后房颤组患者术后机械通气时间、术后住院时间分别为(24.7±14.3) h、(9.1±3.6) d,均大于无术后房颤组[(19.6±9.5) h、(7.6±2.9) d];置换机械瓣患者比例为85.7%(24/28),低于无术后房颤组[96.7%(88/91)],置换生物瓣膜患者比例为14.3%(4/28),高于无术后房颤组[3.3%(3/91)],2组比较差异均有统计学意义(P<0.05);术后房颤组患者术后行开胸止血术的比例为3.6%(1/28),高于无术后房颤组[2.2%(2/91)],2组比较差异无统计学意义(P>0.05)。(4)采用ROC曲线对内皮素-1预测术后新发房颤的价值进行分析可得,曲线下面积为0.76,95%CI：0.66～0.85,截断值0.265 pmol/L,特异度0.75,敏感度0.63。根据截断值将患者分为内皮素-1>0.265组(n＝55)和内皮素-1<0.265组(n＝64),对2组患者术前、术中资料和术后资料进行比较,结果可得内皮素-1>0.265组患者左心房直径大于内皮素-1<0.265组患者,主动脉瓣狭窄患者比例低于内皮素-1<0.265组患者,术后新发房颤的发生率(38.2%)明显高于内皮素-1<0.265组(10.9%),差异均有统计学意义(P<0.05),其他各项比较差异均无统计学意义(P>0.05)。对收集到的患者资料进行单因素Logistic回归分析,发现年龄、NYHA分级≥3级、左心房直径、主动脉瓣狭窄、术后机械通气时间、置换生物瓣及内皮素-1>0.265 pmol/L均与术后新发房颤的发生相关;对以上指标进行多因素Logistic回归分析结果可得左心房直径、置换生物瓣和内皮素-1>0.265 pmol/L与患者术后新发房颤的发生呈独立相关。 结论在单纯行单纯主动脉瓣置换术的患者中,除左心房直径、置换生物瓣外,较高的内皮素-1水平也是患者发生术后新发房颤的独立危险因素。     

Prognostic value of low-dose dobutamine stress echocardiography in patients with aortic stenosis and impaired left ventricular function

Introduction

The aim of this multicenter, prospective study was to evaluate the long-term prognostic value of low-dose dobutamine stress echocardiography (LDDSE) in patients with aortic stenosis (AS) and depressed left ventricular (LV) function.

Material and methods

The study group comprised 39 patients (34 male, mean age 59 ±13 years) with AS (peak gradient > 25 mm Hg), LV ejection fraction (LVEF) ≤ 45% and low transaortic gradient (peak gradient ≤ 45 mm Hg, mean gradient ≤ 35 mm Hg). The qualification for subsequent therapeutic procedures was based on generally accepted indications. All patients underwent LDDSE and coronary angiography. Twelve months after LDDSE patients underwent control resting echocardiography and clinical evaluation.

Results

Twenty-seven (69.2%) patients had preserved contractile reserve. In this subgroup, true-severe AS was diagnosed in 12 patients, whereas pseudo-severe AS was found in 15 patients. Nine patients with true-severe AS, 2 patients with pseudo-severe AS and 7 patients without contractile reserve were referred for surgical treatment. The independent risk factors of death during follow-up were: aortic valve area (AVA) at peak stress < 0.8 cm² (OR 1.4; p = 0.003) and LVEF at rest < 35% (OR 6.8; p = 0.05). The independent risk factors of composite end-point (death or myocardial infarctions or pulmonary edema) were: AVA at stress < 0.8 cm² (OR 4.0; p = 0.03), absence of AVA increase during LDDSE (OR 5.7; p = 0.005), absence of contractile reserve (OR 4.5; p = 0.01) and presence of significant CAD (OR 6.9; p = 0.02).

Conclusions

In patients with AS and depressed LVEF, LDDSE is a useful tool for long-term risk stratification.     

Relationship between the membranous septum and the virtual basal ring of the aortic root in candidates for transcatheter implantation of the aortic valve

Knowledge of the anatomy of the membranous septum, as a surrogate to the location of the atrioventricular conduction axis, is a prerequisite for those undertaking transcatheter implantation of the aortic valve (TAVI). Equally important is its relationship of the virtual basal ring. This feature, however, has yet to be adequately described in the living heart. We analyzed computed tomographic angiographic datasets from 107 candidates (84.1 ± 5.2 years, 68% women) for TAVI. Using multiplanar reconstructions, we measured the height and width of the membranous septum, and the distances of its superior and inferior margins from the virtual basal ring plane. We also assessed the extent of wedging of the aortic root between the mitral valve and the ventricular septum. Mean heights and widths of the membranous septum were 6.6 ± 2.0, and 10.2 ± 3.1 mm, respectively, with its size significantly associated with that of the aortic root (P < 0.05). Its superior and inferior margins were 4.5 ± 2.3 and 2.1 ± 2.1 mm, respectively, from the plane of the basal ring. The inferior distance, the surrogate for the adjacency of the atrioventricular conduction axis, was ≤ 5mm in 91% of the patients. Deeper wedging of the aortic root was independently correlated with a shorter inferior distance (β = 0.0569, P = 0.0258). The membranous septum is appreciably closer to the virtual basal ring than previously appreciated. These findings impact on estimations of the risk of damage to the atrioventricular conduction axis during TAVI. Clin. Anat. 31:525–534, 2018. © 2018 Wiley Periodicals, Inc.     

Characteristics of cavitation intensity in a mechanical heart valve using a pulsatile device: synchronized analysis between visual images and pressure signals

To investigate the characteristics of cavitation intensity, we performed a synchronized analysis of the visual images of cavitation and the pressure signals using a pulsatile device. The pulsatile device employed was a pneumatic ventricular assist device (PVAD) that is currently being developed by our group. A 23-mm Medtronic Hall valve (M-H valve) and a 23-mm Sorin Bicarbon bileaflet valve (S-B valve) were mounted in the inlet port of the PVAD after the sewing ring had been removed. A function generator provided a square signal, which was used as the trigger signal, via Electrocardiogram R wave (ECG-R) mode, of the control - drive console for circulatory support. The square signal was also used, after a suitable delay, to synchronize operation of a pressure sensor and a high-speed video camera. The data were stored using a digital oscilloscope at a 1-MHz sampling rate, and then the pressure signal was band-pass filtered between 35 and 200 kHz using a digital filter. The valve-closing velocity, visual cavitation time, and root mean square (RMS) pressure of the M-H valve were greater than those of the S-B valve. Both the visual cavitation time and RMS pressure represent the cavitation intensity, and this is a very important factor when estimating mechanical heart valve cavitation intensity in an artificial heart.     

Interaction between the aortic valve leaflets and a Millar dual-micromanometer catheter during recording of the aortic component of the second heart sound in dogs

The influence of the closure of the aortic valve leaflets on a dual-micromanometer Millar catheter is investigated with respect to the power spectrum of the aortic component (A2) of the second heart sound in dogs. The catheter inserted through the aortic valve is used to simultaneously record A2 in the left ventricle and in the aorta and to study the transmission of A2 up to the body surface. Results indicate that the interaction of the valve leaflets with the Millar dual-micromanometer catheter during the closure and vibration of the aortic valve does not produce a clapping artefact. The main effect is a change in the natural modes of vibration (resonant frequencies) of the aortic valve resulting from a modification of the vibrating structure (combined structure composed of the catheter, the aortic valve and the surrounding blood and tissues) because of the tight mechanical coupling between the aortic valve leaflets and the catheter. In addition, this modification of the natural modes of resonance does not invalidate the estimation of the frequency response of the transfer function between the aortic root and the thoracic recording site, even if the mean gain of the transfer function is affected and the phase slightly increased with frequency. On the contrary, the interaction of the aortic valve leaflets with the catheter seems to slightly increase the spectral contribution (coherence) of the intra-aortic A2 to the thoracic A2.