左心辅助对犬右心室的影响

目的 :观察左心辅助对犬右心室的影响。方法 :2 1条健康犬按不同左心辅助流量随机分为 3组 ,每组 7条。Ⅰ组辅助流量为 5 0ml·kg- 1 ·min- 1 ;Ⅱ组辅助流量为 70ml·kg- 1 ·min- 1 ;Ⅲ组辅助流量为 90ml·kg- 1 ·min- 1 。应用气动左心辅助装置行左心房至升主动脉辅助 5h。观察辅助前 ,辅助 5h ,停辅助 10min等时间位点的右心血流动力学变化。结果 :辅助 5h ,Ⅰ、Ⅱ、Ⅲ组左房压 (LAP) ,平均肺动脉压 (MPAP) ,全肺阻力 (TPR) ,右室最大压力上升速率 (Rvdp dtmax)均较辅助前明显减小 (P <0 0 5 ) ,且辅助流量越大下降幅度越明显 (P <0 0 5 ) ,Ⅰ、Ⅱ组右心排血指数 (PCI)较辅助前明显增高 (P <0 0 5 ) ,Ⅲ组无明显变化 (P >0 0 5 ) ,Ⅰ、Ⅱ组右心搏动指数 (RCWI)无明显变化 (P >0 0 5 ) ,Ⅲ组明显减小 (P <0 0 5 ) ,停辅助 10min时各组右心血流动力学指标均恢复至辅助前 (P >0 0 5 )。结论 :左心辅助流量越大对右心血流动力学影响越明显 ,短期左心辅助不会导致右心室的功能减退     

一氧化氮合酶2抑制剂对大鼠心肌梗死后左心室形态及心功能的影响

目的：观察选择性一氧化氮合酶2（NOS2）抑制剂S-甲基硫脲（SMT）对心肌梗死（MI）后左心室形态学和血流动力学指标的影响，探讨NOS2在MI后心功能障碍形成过程中的作用。方法： 于大鼠冠状动脉结扎前30 min给予SMT灌胃，6周后测定左心室形态学和血流动力学指标、心肌NOS2表达量、血浆NO2-/NO3-水平、心肌纤维化程度。结果： MI后6周，心脏非梗死区NOS2表达量、血浆NO2-/NO3-水平、中心静脉压和左室舒张末压高于对照组。使用SMT可降低血浆NO2-/NO3-水平［(26.6±6.1） μmol/L vs （50.1±10.4） μmol/L, P＜0.01］，减少心肌梗死范围（36.0%±7.2% vs 42.6%±8.6%, P＜0.05），减轻心室扩张［LVD，（6.6±0.3） mm vs （7.2±0.3） mm, P＜0.01］，减小心肌细胞直径［(15.1±1.6） μm vs （16.9±2.3） μm, P＜0.05］，减轻心肌纤维化［CVF，4.1%±1.1% vs 5.7%±1.2%, P＜0.01］，降低中心静脉压［（0.9±0.3） mmHg vs （1.5±0.5） mmHg, P＜0.01］和左室舒张末压［（8.1±2.4） mmHg vs（13.4±3.1） mmHg, P＜0.01］，提高存活率（72.4% vs 39.3%, P＜0.05）。结论： 大鼠MI后，NOS2可能起促进心功能障碍形成的作用。抑制NOS2可以减轻心室重构，改善心功能。     

猪低中心静脉压动物模型的建立

 目的 建立猪低中心静脉压（CVP）模型，研究低 CVP 技术对猪肝脏手术期间肝静脉出血量及血流动力学的影响。 方法 研究采用自身对照设计。取健康巴马小型猪 16 只，全麻后气管内插管，左侧股动脉切开置管监测平均动脉压；右侧颈内静脉切开，置漂浮导管监测肺动脉压、肺动脉楔压、心排出量和 CVP 等血流动力学参数；开腹分离肝左静脉置管，观察肝静脉压和单位时间内肝静脉出血量。采用经微量输液泵输注不同剂量硝酸甘油结合调节输液速度的方法将CVP 调控在低（< 5 cm H₂O ）、正常（5 ~ 10 cm H₂O）两个不同水平，观察不同水平 CVP 对肝静脉压、肝静脉出血量和血流动力学参数的影响。 结果 动物成模率为 100%。CVP 处于 < 5 （4.26 ± 1.01）、5 ~ 10（8.32 ± 1.86）cm H₂O 水平时，肝静脉压（cm H₂O）分别为 4.40 ± 1.05、8.59 ± 1.92，左肝静脉出血量（ml·min^-1）分别为40.4 ± 5.7、52.9 ± 9.6，差异均有统计学意义（P < 0.01）。CVP从 5 ~ 10 cm H₂O 降至 < 5 cm H₂O 时，肺动脉压（mm Hg）由 20.86 ± 5.02 降至 16.50 ± 3.20 （P < 0.01），肺动脉楔压（mm Hg）由 9.93 ± 2.76 降至 7.14 ± 1.61（P < 0.01），心排出量、心率、平均动脉压无明显变化。 结论 成功建立了猪低中心静脉压动物模型，证实在肝脏手术中采用低 CVP 技术有助于减少肝静脉出血量，而对模型动物血流动力学无明显影响。     

新型气动左心辅助循环装置动物存活实验

目的　应用自行研制的气动左心辅助泵 (罗叶泵 )进行动物存活实验 ,探讨其对血流动力学、血液有形成分和肝肾功能的影响及其临床应用的可行性 ;方法　健康山羊 12只 ,体重 2 9.7～ 39.4kg ,平均 34.1kg ,从左心房至降主动脉间转流 ,进行左心辅助循环 (LVAD) ,辅助频率为 6 0次 /分 ,流量为 2～ 3L/min ;结果　本组山羊LVAD时间为 13～174小时 ,平均 89小时 ,LVAD过程中 ,动物血压、中心静脉压稳定 ,尿液正常 ,肝肾病理检查未见坏死及出血灶 ;肌酸激酶同功酶、乳酸脱氢酶在辅助 4 8小时较术前明显升高 ,分别为 396 8.70± 15 6 1.2 5U/L ,2 0 18 0 0± 6 4 9 12U/L ,但 72小时后逐渐恢复正常 ,游离血红蛋白LVAD 4 8小时为 4 81 12± 116 .16mg/L ,在LVAD 72小时降至正常范围 (2 91.13±12 1.13mg/L) ;结论　罗叶泵能有效地维持血流动力学稳定 ,性能稳定、可靠 ,说明该血泵已具备条件进行短期临床试用     

体外反搏对犬血流脉动性和血管阻力的影响

为了评价体外反搏是否具有扩张血管和增加血流脉动性的作用 ,制造了犬急性心肌梗塞模型 ,并使犬存活 6周。麻醉后 ,测定左侧颈总动脉血流量和右侧颈总动脉血压。计算反搏前和反搏中脉压差、血压脉动指数、血压的标准差、流量差、流量脉动指数、流量标准差和平均血管阻力。结果显示脉压差、血压脉动指数和血压标准差三个血压脉动性指标分别由反搏前的 30± 9mm Hg、1.2 6± 0 .0 5、8.7± 2 .5 mm Hg升高到反搏中的 4 3± 8mm Hg(P<0 .0 5 )、1.5 4± 0 .13、12 .4± 2 .0 mm Hg (P<0 .0 5 )。流量差、流量脉动指数和流量标准差三个血流脉动性指标分别由反搏前的 317± 4 8ml/ min、2 .85± 0 .2 1、96± 2 1ml/ min升高到反搏中的 4 4 7± 88m l/ min、4 .5 6± 0 .90、131±39m l/ m in,P值均于小 0 .0 5。平均血管阻力由反搏前的 5 78± 72 Wood单位降低到反搏中的 4 76± 85 Wood单位(P<0 .0 5 )。这表明体外反搏可使血管阻力下降 ,血压和血流脉动性增强。     

用快速心室搏研制充血性心力衰竭兔模型

建立充血性心力衰竭 (CHF)兔模型。用人工体外心脏起搏方法 ,持续快速心室起搏 3周 (P组 ,n =7) ,观察心脏大小及血流动力学变化 ,另以假手术组对照 (C组 ,n =9)。心脏体积、左室舒张末压 (LVEDP ,mmHg)、中心静脉压 (CVP ,mmHg) ,P组均分别高于C组 (P <0 0 1) ,而左室射血分数 (LVEF ,% )、左室短轴缩短率 (LVFS ,% )、心输出量 (CO ,mL/min)、主动脉平均压力 (MAP ,mmHg)及左室压力微分 (±dp/dt,mmHg/s)均分别显著低于C组 (P <0 0 1) ,提示通过持续快速心室起搏的方法可以建立CHF兔模型。     

利用容量型肺动脉导管监测心室压力-容量关系的研究与应用

20世纪70年代Swan和Ganz两人从港湾帆船漂流得到启示,发明了肺动脉漂浮导管(Swan-Ganz catheter),最初只能测肺动脉血压和采血样.通过中心静脉压(central venous pressure,CVP)了解右心前负荷;通过肺动脉楔压(pulmonary anery wedge pressure,PAWP)了解左心前负荷.随后利用温度稀释法实现了测量心排血量(cardiac output,CO).CO测定的出现给血流动力学监测带来了重大变革.很多数据都可以通过CO计算出来.     

左心旁路期间右心室的功能

心脏在靠机械泵维持左心室功能期间,可能发生右心衰竭。为了探索右心功能的变化,用一个滚动泵在8只狗(26.9±1.4公斤)身上做不同程度的左心傍路(LHBP)实验。用一辅助泵控制静脉血回流到右房,右室功能由右室峰压、右室峰压的一次导数(dp/dt)和右房平均压的大小来评价,并且测定左心房压、左心室压、主动脉压以及2个滚动泵的流量,左心傍路流量比率(LHDP流量×100/静脉返流量)增长到60%、90%、甚至100%,分别与右室dp/dt从每秒212±17脱减少到192±16脱、178±16脱和168±13脱有关。如果为保持机体有足够的血流供应而要求LHBP流量比率大于90%     

大鼠心肌梗死后心肌NADPH氧化酶亚单位p22phox的表达

目的：探讨心肌梗死大鼠心室重塑与还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶亚单位p22phox和超氧阴离子的关系。 方法： Sprague-Dawley大鼠冠脉左前降支结扎复制心肌梗死模型，8周后，心脏超声、血流动力学、心脏形态学方法检测分析心室重塑，检测血浆和非梗死心肌脂质过氧化物的浓度。用RT-PCR和免疫组化方法检测p22phox mRNA水平和蛋白水平的分布。用激光共聚焦方法检测心肌超氧阴离子分布。 结果： 心肌梗死后大鼠心室重塑过程显著，与正常对照组比较，左室舒张末压、左室舒张末径［(3.09±1.52 vs 18.24±6.58)mmHg，(0.67±0.06 vs 0.90±0.15)mm, P<0.01］和脂质过氧化物水平在血浆和非梗死心肌均显著大于正常对照组(P<0.05)。p22phox mRNA和蛋白表达以及超氧阴离子分布在梗死和非梗死心肌亦均显著增加。 结论： 大鼠心肌梗死后，NADPH氧化酶表达增高，其来源的超氧阴离子可能通过氧化应激参加心室重塑过程。     

The Antithrombosis Function and Hemodynamic Propertiesof the Luo-Ye Pump

作者采用新型左心辅助泵－罗叶泵在动物体内进行左心辅助循环活体实验，用健康山羊１０只，体重３０～５３ｋｇ，平均４３．５ｋｇ。全组动物均应用左心房与降主动脉间转流。结果如下：１．１０只山羊术前与转流后６小时平均动脉压分别是１３．３±０．８ｋＰａ１３．６±１．９ｋＰａ，中心静脉压分别是１．７３±０．１４ｋＰａ和０．８２±０．３１ｋＰａ；２．术前和转流后左心室舒张期内径长轴分别为５８．１±１．９ｍｍ和３９．３±１．５ｍｍ，短轴分别为２５．０±１．２ｍｍ和１８．１±１．４ｍｍ；３．术前及转流后动脉血气分析均在正常范围；４．ＡＣＴ和ＰＴ时间在术后２～３小时均降至正常水平；５．辅助循环后血浆游离血红蛋白浓度有不同程度升高，最高达２２４．５±４０．８ｍｇ／Ｌ；６．病理检查未见血栓形成和栓塞现象。结果显示为罗叶泵具有良好的抗血栓形成作用和良好的血流动力学特性。是很好的左心辅助泵并具有良好的临床应用前景。     

Biventricular support with the Jarvik 2000 axial flow pump: a feasibility study

Patients with congestive heart failure who are supported with a left ventricular assist device (LVAD) may experience right ventricular dysfunction or failure that requires support with a right ventricular assist device (RVAD). To determine the feasibility of using a clinically available axial flow ventricular assist device as an RVAD, we implanted Jarvik 2000 pumps in the left ventricle and right atrium of two Corriente crossbred calves (approximately 100 kg each) by way of a left thoracotomy and then analyzed the hemodynamic effects in the mechanically fibrillated heart at various LVAD and RVAD speeds. Right atrial implantation of the device required no modification of either the device or the surgical technique used for left ventricular implantation. Satisfactory biventricular support was achieved during fibrillation as evidenced by an increase in mean aortic pressure from 34 mm Hg with the pumps off to 78 mm Hg with the pumps generating a flow rate of 4.8 L/min. These results indicate that the Jarvik 2000 pump, which can provide chronic circulatory support and can be powered by external batteries, is a feasible option for right ventricular support after LVAD implantation and is capable of completely supporting the circulation in patients with global heart failure.     

Clinical evaluation of right ventricular function in patients with left ventricular assist device (LVAD).

Right ventricular function (RVF) during LVAD support can be a threat for patient survival. Despite extensive research, RVF and its interference with left heart function is unclear. This study examines RVF in a retrospective analysis of 14 patients. Hemodynamic data were collected, including heart rate (HR), central venous pressure (CVP), mean pulmonary artery pressure (mPAP), total cardiac output (CO), calculated stroke volume index (SVI) and right ventricular stroke work index (RVSWI). In all patients, CO increased gradually throughout the study period; CVP showed no significant decrease; mPAP and PCWP decreased significantly over the time period; SVI improved and RVSWI increased from the starting level prior to implantation of the LVAD. We conclude that the CO improved with a lowering of the right ventricular afterload combined with a decrease in total circulating volume. The improvement of RVF with LV assist makes this device an option as a bridge to transplant.     

Acute in vivo evaluation of an implantable continuous flow biventricular assist system

An implantable biventricular assist device offers a considerable opportunity to save the lives of patients with combined irreversible right and left ventricular failure. The purpose of this study was to evaluate the hemodynamic and physiologic performance of the combined implantation of the CorAide left ventricular assist device (LVAD) and the DexAide right ventricular assist device (RVAD). Acute hemodynamic responses were evaluated after simulating seven different physiological conditions in two calves. Evaluation was performed by fixing the speed of one individual pump and increasing the speed of the other. Under all conditions, increased LVAD or RVAD speed resulted in increased pump flow. The predominant pathophysiologic effect of independently varying DexAide and CorAide pump speeds was that the left atrial pressure was very sensitive to increasing RVAD speed above 2,400 rpm, whereas the right atrial pressure demonstrated much less sensitivity to increasing LVAD speed. An increase in aortic pressure and RVAD flow was observed while increasing LVAD speed, especially under low contractility, ventricular fibrillation, high pulmonary artery pressure, and low circulatory blood volume conditions. In conclusion, a proper RVAD-LVAD balance should be maintained by avoiding RVAD overdrive. Additional studies will further investigate the performance of these pumps in chronic animal models.     

Atrial, ventricular, or both cannulation sites to optimize left ventricular assistance?

The efficiency of left ventricular assist devices (LVADs) depends on the capacity of the inflow cannula to drain blood into the pump. Left atrial (LA) and left ventricular (LV) sites were compared in an animal model mimicking different hemodynamic conditions. Three calves (56.3+/-5.0 kg) were equipped with a Thoratec LVAD. A regular cardiopulmonary bypass (CPB) circuit was used as a right ventricular assist device (RVAD) (jugular vein/pulmonary artery), and preload conditions were adjusted by storage (or perfusion) of blood into (or from) the venous reservoir. LA and LV drainage, tested separately or simultaneously, was measured by its effect on the LVAD's performance. The LVAD was used alone on a beating heart or together with the RVAD (biVAD) on a beating and on a fibrillating heart. Increasing the central venous pressure (CVP) highlighted the differences between the LA and LV cannulation sites when the LVAD was tested either alone or together with the RVAD (biVAD) on a beating heart. Drainage through the LA or the LV was similar when CVP was set at 8 mm Hg, and increasing CVP to 14 mm Hg allowed for better drainage through the LV cannula. In contrast, after induction of fibrillation to mimic extreme heart failure, the drainage was better through the LA cannula. Using both LA and LV cannulae simultaneously did not improve the LVAD output in any of the conditions tested. LV cannulation provides better blood drainage when used on a normal beating heart and, therefore, allows for increased LVAD performance. However, in severe heart failure, blood drainage through the LV cannula decreases and the LA cannulation site is superior.     

The fourth-generation centrifugal blood pump

 The NEDO Gyro permanently implantable (PI) centrifugal blood pump has been developed as a simple, durable, centrifugal blood pump without a complex magnetic suspension system. In vitro studies were performed using a Gyro PI pump with the transparent pump housing in a mock circuit. These studies revealed that the impeller transfers to a floating or a top contact condition, which was dependent on the revolutions per minute (RPM). This pump can be easily converted from a left ventricular assist device (LVAD) to a right ventricular assist device (RVAD) by simply adding a spacer between the pump and the actuator. In order to optimize the impeller suspension for the LVAD and RVAD, spacers of the proper thickness are inserted between both of the pumps and the actuators to regulate the magnetic force. Two Gyro PI pumps were implanted in a bovine model in a 3-month biventricular assist device (BVAD) animal study. This experiment was electively terminated 90 days after implantation. All of the parameters, including pump flow rate, power consumption, and plasma free hemoglobin, were in acceptable ranges. No thrombus formation was observed in either pump. Antithrombogenesis and effectiveness were demonstrated in this animal study. The NEDO Gyro PI pump is ready to move on to the 3-month preclinical system evaluation. Received: February 28, 2002 / Accepted: May 30, 2002 Acknowledgment The New Energy and Industrial Technology Development Organization (NEDO) under the Ministry of Economy, Trade and Industry of Japan financially supported this project. Correspondence to:S. Ichikawa     

Discontinuation of HeartWare RVAD support without device removal in chronic BIVAD patients

During biventricular assist device (BVAD) support, right ventricular (RV) assistance may restore sufficient RV function after several weeks to months. Since November 2009, 10 patients (9 men and 1 woman; mean age, 49.7 ± 14.4 y) suffering from idiopathic dilatative cardiomyopathy received BVAD employing two implantable continuous-flow pumps of the HeartWare type. In three male patients, aged 53, 57, and 60 years, after a right ventricular assist device (RVAD) support time of 15.6, 11.2, and 3.6 months, respectively, the RVAD was stopped, and the percutaneous lead was surgically shortened in two cases. There were no differences in preoperative RV geometry and function or in severity of tricuspid valve regurgitation in patients with and without delayed RV recovery. Follow-up echocardiography revealed no regurgitation through the right pump in any patient. One patient died due to severe sepsis 63 days later; the other two patients are currently on left ventricular assist devices support at home, 120 and 236 days after RVAD deactivation with stable hemodynamic conditions and without any thromboembolic events. RV function may recover even after weeks or months on BVAD support. The HeartWare HVAD used as an RVAD may be stopped and left in place without complications.     

Prediction of outcome in patients with liver dysfunction after left ventricular assist device implantation

Although postoperative liver dysfunction (LD) following left ventricular assist device (LVAD) implantation is associated with high mortality, outcome is difficult to predict in patients with liver dysfunction. We aimed to clarify factors affecting recovery from LD after VAD implantation. A total of 167 patients underwent LVAD implantation, of whom 101 developed early postoperative LD, defined as maximum total bilirubin (max T-bil) greater than 5.0 mg/dl within 2 weeks. We set two different end-points, unremitting LD, and 90-day mortality. The rates of early mortality (90 days) and recovery from LD were 36 % (36/101) and 72 % (73/101), respectively. Univariate analysis showed that preoperative body weight, preoperative mechanical support, preoperative T-bil and creatinine, left ventricular diastolic dimension, right VAD (RVAD) insertion, cardiopulmonary bypass time, postoperative cardiac index, and postoperative T-bil and central venous pressure (CVP) on postoperative day (POD) 3 (non-recovered vs recovered, 12.4 ± 4.5 vs 9.5 ± 3.6 mmHg) were higher in patients with unremitting LD. Preoperative T-bil, RVAD insertion, and T-bil and CVP on POD 3 (non-survivor vs survivor, 12.4 ± 4.4 vs 9.4 ± 3.6 mmHg) were also higher in non-survivors. Multivariate analysis demonstrated that CVP on POD 3 was predictive of recovery from postoperative LD (OR 0.730, P < 0.05) and 90-day mortality (OR 0.730, P < 0.05). A key outcome factor in patients who developed early postoperative LD after LVAD implantation was postoperative liver congestion with high CVP. To overcome postoperative LD, appropriate management of postoperative CVP level is important.     

Successful use of temporary right ventricular support to avoid implantation of biventricular long-term assist device: a transcutaneous approach

Severe right ventricular (RV) failure after left ventricular assist device (LVAD) implantation is a serious complication with a poor prognosis. The most effective therapy for these patients is an upgrade to biventricular mechanical support. However, it is well recognized that primary and secondary biventricular ventricular assist device implantation is associated with higher mortality rates. We report on three patients with cardiogenic shock, who were provided on an emergency basis with a percutaneous extracorporeal life support (ECLS) system by the femoral vessels. After stabilization, a LVAD was implanted. To avoid secondary RV failure, the ECLS was switched to a transcutaneous RV assist device (RVAD) as a temporary RV support. The arterial cannula was removed from the femoral artery, and a prosthesis-supported cannula was sutured to the pulmonary artery and passed through a subxiphoid exit. The femoral vein cannula was left in situ. Both cannulae were connected to a centrifugal pump. Two patients could be weaned from the RVAD; the system was explanted under local anesthesia. One patient died due to internal bleeding. In conclusion, the ease of device implantation, weaning, and explantation justifies a liberal use of temporary RV support to avoid implantation of the problematic long-term biventricular assist devices.     

Prerequisites to salvage profound biventricular failure patients with ventricular assist devices

We conducted chronic experiments to determine how to treat profound biventricular failure systematically with ventricular assist devices (VADs) and to analyze the factors that affect prognoses for this condition. Anoxic arrest was induced in ten goats by aortic cross-clamping under normothermic conditions (38.5 degrees C) for 30 (n = 3), 45 (n = 1), and 60 (n = 6) minutes. A left ventricular assist device (LVAD) was implanted in eight animals, and a biventricular assist device (BVAD) was used in two. Three goats--two of which had undergone anoxic arrest for 30 minutes and one for 60 minutes--whose right atrial pressure (RAP) was approximately 18 mm Hg during the acute stage, recovered in two to three weeks, and the pumps were successfully removed. Pathological findings in these animals showed scattered areas of surviving myocardium, with connective tissue replacing the degenerated myocardium. The remaining five LVAD goats required higher RAPs to maintain circulation and died from various causes. Maintaining circulation without volume loading, even in the presence of arrhythmias, was easier with the BVAD. One BVAD animal that underwent 45 minutes of anoxic arrest recovered from right ventricular failure, and the right pump was removed. The second goat (anoxic arrest, 60 min) on the BVAD failed to recover. Autopsy of the myocardium revealed a thin ventricular wall. Our studies show that the use of VADs allows time for a failing heart to recover, but the potential for healing is affected by the severity of myocardial damage prior to VAD application.(ABSTRACT TRUNCATED AT 250 WORDS)     

Development of a small implantable right ventricular assist device

The purpose of this program is to design, develop, and clinically evaluate a new, implantable right ventricular assist device (RVAD) that can be used as a component of an implantable biventricular assist device for patients with severe biventricular heart failure. The initial phase of this program resulted in a prototype RVAD, named DexAide, a modified version of the CorAide left ventricular assist device. In vitro testing was performed in a stand-alone circuit and in a true RVAD mode to evaluate pump performance. Pump flow and power were measured under various afterload and pump speed conditions. The pump performance requirements of 2 to 6 l/min and a pressure rise of 20 to 60 mm Hg were successfully met with pump speeds between 1,800 and 3,200 rpm. The nominal design point of 4 l/min and 40 mm Hg pressure rise was achieved at 2,450 +/- 70 rpm with a power consumption of 3.0 +/- 0.2 W. The initial in vitro testing met the design criteria for the new DexAide RVAD. Initial in vivo testing is under way, which will be followed by preclinical readiness testing and a pilot clinical trial in this 5-year program.