Right ventricular dysfunction after cardiac transplantation: primarily related to status of donor heart

BACKGROUND: It is unclear whether right ventricular dysfunction after transplantation is due to donor brain death-related myocardial injury or recipient pulmonary hypertension. METHODS: A canine donor model of brain death and a monocrotaline pyrrole-induced chronic pulmonary hypertension recipient model were established, and used for 30 orthotopic bicaval cardiac transplantations divided into three groups: Controls (group A, normal donor/recipient), group B (brain-dead donors/normal recipient), and group C (normal donor/recipients with pulmonary hypertension). Right ventricular function was measured before transplant and brain death, 4 hours after brain death, and after transplant (1 hour off bypass) by load-independent means plotting stroke work versus end-diastolic volume during caval occlusion. Right ventricular total power and pulmonary vascular impedance were determined by Fourier analysis. RESULTS: In comparison to the control group right ventricular preload-recruitable stroke work and total power decreased significantly after brain death and transplant in group B (from 22.7 x 10(3) erg (+/-1.2) at baseline to 15.6 x 10(3) (+/-0.9) after brain death and to 11.3 x 10(3) (+/-0.9) after transplant). In group C there was a significant increase in pulmonary artery pressure, impedance, right ventricular preload-recruitable stroke work, total power after transplant. CONCLUSIONS: Normal donor hearts adapt acutely to the recipient's elevated pulmonary vascular resistance by increasing right ventricular power output and contractility. Brain death caused significant right ventricular dysfunction and power loss, which further deteriorated after graft preservation and transplantation. The effects of donor brain death on myocardial function contribute to right ventricular dysfunction after cardiac transplantation.     

Effects of Nitric Oxide After Cardiac Transplantation in the Setting of Recipient Pulmonary Hypertension

Background. Recipient pulmonary hypertension secondary to chronic congestive heart failure is a significant risk factor for right ventricular failure after cardiac transplantation. In this study, the hemodynamic and inotropic effects of nitric oxide (NO) were examined after bicaval cardiac transplantation in the setting of monocrotaline pyrrole-induced recipient chronic pulmonary hypertension.

Methods. Twenty dogs underwent 10 successfully completed transplantation experiments. Recipients underwent pulmonary artery injection of 3 mg/kg monocrotaline pyrrole 4 months before transplantation. Measurements were taken 1 hour after cessation of cardiopulmonary bypass and after NO inhalation. Pulmonary vascular impedance was calculated using Fourier analysis, and cardiac function was assessed with load-insensitive means (preload recruitable stroke work).

Results. At the time of transplantation, the precardiopulmonary bypass levels of pulmonary vascular resistance in recipient animals were significantly greater when compared with donor levels, and were further significantly increased after cardiopulmonary bypass. Three recipients died after transplantation secondary to acute right ventricular failure. In the surviving animals, NO led to significant improvements in pulmonary vascular resistance and vascular impedance, which occurred in association with significant increases in transpulmonary efficiency. No significant changes were observed in right and left ventricular preload recruitable stroke work after NO inhalation.

Conclusions. These data suggest that NO may be an effective means to improve vascular impedance and pulmonary vascular efficiency after cardiac transplantation in the setting of recipient chronic pulmonary hypertension.     

Effects of Nitric Oxide After Cardiac Transplantation in the Setting of Recipient Pulmonary Hypertension

Background. Recipient pulmonary hypertension secondary to chronic congestive heart failure is a significant risk factor for right ventricular failure after cardiac transplantation. In this study, the hemodynamic and inotropic effects of nitric oxide (NO) were examined after bicaval cardiac transplantation in the setting of monocrotaline pyrrole-induced recipient chronic pulmonary hypertension.Methods. Twenty dogs underwent 10 successfully completed transplantation experiments. Recipients underwent pulmonary artery injection of 3 mg/kg monocrotaline pyrrole 4 months before transplantation. Measurements were taken 1 hour after cessation of cardiopulmonary bypass and after NO inhalation. Pulmonary vascular impedance was calculated using Fourier analysis, and cardiac function was assessed with load-insensitive means (preload recruitable stroke work).Results. At the time of transplantation, the precardiopulmonary bypass levels of pulmonary vascular resistance in recipient animals were significantly greater when compared with donor levels, and were further significantly increased after cardiopulmonary bypass. Three recipients died after transplantation secondary to acute right ventricular failure. In the surviving animals, NO led to significant improvements in pulmonary vascular resistance and vascular impedance, which occurred in association with significant increases in transpulmonary efficiency. No significant changes were observed in right and left ventricular preload recruitable stroke work after NO inhalation.Conclusions. These data suggest that NO may be an effective means to improve vascular impedance and pulmonary vascular efficiency after cardiac transplantation in the setting of recipient chronic pulmonary hypertension.(Ann Thorac Surg 1997;63:1546–55)     

Early effects of right ventricular volume overload on ventricular performance and beta-adrenergic signaling

OBJECTIVE: Right ventricular dysfunction is a poorly understood but persistent clinical problem. This study was undertaken to evaluate ventricular performance and beta-adrenergic receptor signaling in a tricuspid regurgitation model of right ventricular overload. METHODS: Seventeen dogs were chronically instrumented with epicardial dimension transducers. By means of the shell-subtraction model, right ventricular pressure-volume relationships were evaluated in normal and right ventricular overload states. Right ventricular chamber performance was quantified by the stroke work at an end-diastolic volume relationship. RESULTS: Right ventricular volume overload caused a 28% +/- 11% and 31% +/- 9% decline in chamber performance acutely and at 1 week, respectively, whereas end-diastolic volume increased from 45 +/- 21 to 60 +/- 30 mL (P =. 019). beta-Adrenergic receptor signaling in myocardial samples was assessed, examining adenylyl cyclase and G-protein-coupled receptor kinase activity. Stimulated adenylyl cyclase activity significantly decreased, and G-protein-coupled receptor kinase activity significantly increased in both left and right ventricular samples caused by increased levels of beta-adrenergic receptor kinase 1. No change in beta-adrenergic receptor density was seen at 1 week. CONCLUSIONS: Early right ventricular overload is associated with impaired right ventricular chamber contractility, dilation, and, importantly, a biventricular alteration of beta-adrenergic receptor signaling.     

Right ventricular targeted gene transfer of a beta-adrenergic receptor kinase inhibitor improves ventricular performance after pulmonary artery banding

OBJECTIVE: Abrupt increases in right ventricular afterload occur after cardiac transplantation and pulmonary artery banding, which can result in right ventricular hypertrophy and dilatation. Right ventricular dysfunction is also accompanied by beta-adrenergic receptor desensitization. We sought to determine whether selective right ventricular expression of a transgene encoding a beta-adrenergic receptor kinase inhibitor can improve right ventricular remodeling early after pulmonary artery banding. METHODS: Rabbits underwent pulmonary artery banding 3 days after percutaneous right coronary artery injection of empty adenovirus (n = 19), a control adenovirus containing the beta-galactosidase transgene (n = 10), or an adenovirus containing the beta-adrenergic receptor kinase inhibitor transgene (n = 14). Sham-operated animals (n = 7) underwent instrumentation without deployment of the pulmonary artery band. Right ventricular function was assessed in each rabbit before and 7 days after pulmonary artery banding. Right ventricular mass and dimensions (surface area and volume) were obtained, and biochemical analysis was performed to confirm transgene expression and to characterize beta-adrenergic receptor signaling. RESULTS: Right ventricular mass was increased in animals treated with adenovirus containing the beta-adrenergic receptor kinase inhibitor transgene, adenovirus containing the beta-galactosidase transgene, and empty adenovirus after banding when compared with results in sham-operated animals. However, right ventricular volume and surface area, as measures of dilatation, were significantly lower in pulmonary artery banded rabbits pretreated with adenovirus containing the beta-adrenergic receptor kinase inhibitor transgene when compared with those treated with empty adenovirus or adenovirus containing the beta-galactosidase transgene. Right ventricular contractility and defective beta-adrenergic receptor signaling were significantly enhanced in rabbits expressing the beta-adrenergic receptor kinase inhibitor after pulmonary artery banding. CONCLUSIONS: Right ventricular preconditioning with the beta-adrenergic receptor kinase inhibitor transgene can attenuate the early right ventricular dilatation and dysfunction associated with pulmonary artery banding. Thus beta-adrenergic receptor kinase inhibition might represent a novel target for limiting ventricular remodeling after increased right ventricular afterload.     

Angiotensin converting enzyme activity and evolution of pulmonary vascular disease in rats with monocrotaline pulmonary hypertension.

We have investigated the role of angiotensin converting enzyme (ACE) in the development of pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular disease in rats given a single subcutaneous injection of the pyrrolizidine alkaloid monocrotaline. Thirty-six young female Wistar rats were divided into a test group of 27 animals and a control group of nine animals. Each test rat was given a single subcutaneous injection of monocrotaline (60 mg/kg body weight). On the first, third, fifth, seventh, tenth, twelfth, fourteenth, seventeenth, and twenty-second days after the injection of monocrotaline the mean right ventricular systolic blood pressure was measured in one control and three test rats. The animals were then killed and we measured the specific activity of ACE in serum and lung homogenate. We also evaluated muscularisation of pulmonary arterioles, medial hypertrophy of muscular pulmonary arteries, and right ventricular hypertrophy. The sequence of changes was as follows: muscularisation of pulmonary arterioles and medial hypertrophy of muscular pulmonary arteries were apparent seven days after administration of monocrotaline; pulmonary hypertension and reduced lung ACE activity occurred after 10 days; right ventricular hypertrophy was detected after 12 days. Serum ACE activity was unchanged. It is concluded that the reduction in lung ACE activity is a result rather than a cause of the pulmonary hypertension. This reduction in lung ACE activity may be a protective mechanism designed to limit the elevation of the pulmonary arterial pressure.     

The limitations of preload-adjusted maximal power as an index of right ventricular contractility

Right ventricular (RV) dysfunction is an important cause of perioperative morbidity and mortality, particularly in cardiac surgery. However, assessment of RV contractility remains difficult in clinical practice. Our goal in this study was to examine the value of preload-adjusted maximal power (PWR(max)/end-diastolic volume [EDV](2); PAMP) as an alternative to the load-independent pressure-volume-derived indices of contractility in the RV. In anesthetized dogs, RV end-systolic elastance and preload-recruitable stroke work were studied as "gold standards" by using the conductance technique. PAMP was calculated with pulmonary artery flow and RV pressure measurements. Changes in these indices were compared after modulation of the inotropic state (dobutamine infusion; n = 12) and loading conditions (pulmonary artery and inferior caval vein occlusion; n = 14). All indices increased dose-dependently with dobutamine. PAMP was slightly influenced by preload reduction (the slope of the relation between PAMP and EDV was 0.00397 +/- 0.01026 W. mL(-3). 0.10(-4); mean +/- SD). PAMP decreased significantly during pulmonary artery banding (from 1.1 +/- 0.7 to 0.7 +/- 0.5 W. mL(-2). 0.10(-4); mean +/- SD), whereas end-systolic elastance and preload-recruitable stroke work did not change. We conclude that the value of PAMP as an index of RV contractility is limited in the open-chest/open-pericardium setting, primarily by its sensitivity to alterations in afterload. IMPLICATIONS: Preload-adjusted maximal power (PAMP), a load-independent contractile index in the left ventricle, could offer a solution to the problem of measuring right ventricular (RV) contractility in clinical practice. However, this study in open-chest dogs suggests that PAMP is unreliable for assessment of RV contractility because of its sensitivity to afterload changes.     

An artificial lung reduces pulmonary impedance and improves right ventricular efficiency in pulmonary hypertension.

OBJECTIVE: Artificial lungs may have a role in supporting patients with end-stage lung disease as a bridge or alternative to lung transplantation. This investigation was performed to determine the effect of an artificial lung, perfused by the right ventricle in parallel with the pulmonary circulation, on indices of right ventricular load in a model of pulmonary hypertension. METHODS: Seven adult male sheep were connected to a low-resistance membrane oxygenator through conduits anastomosed end to side to the pulmonary artery and left atrium. Banding of the distal pulmonary artery generated acute pulmonary hypertension. Data were obtained with and without flow through the device conduits. Outcome measures of right ventricular load included hemodynamic parameters, as well as analysis of impedance, power consumption, wave reflections, cardiac efficiency, and the tension-time index. RESULTS: The model of pulmonary hypertension increased all indices of right ventricular load and decreased ventricular efficiency. Allowing flow through the artificial lung significantly reduced mean pulmonary artery pressure, zero harmonic impedance, right ventricular power consumption, amplitude of reflected waves, and the tension-time index. Cardiac efficiency was significantly increased. CONCLUSIONS: An artificial lung perfused by the right ventricle and applied in parallel with the pulmonary circulation reduces ventricular load and improves cardiac efficiency in the setting of pulmonary hypertension. These data suggest that an artificial lung in this configuration may benefit patients with end-stage lung disease and pulmonary hypertension with right ventricular strain.     

Right ventricular dynamic cardiomyoplasty for the univentricular heart with pulmonary hypertension

OBJECTIVES: We conducted an acute experimental study to test the feasibility of dynamic cardiomyoplasty in a setting of modified Fontan procedure for univentricular heart with pulmonary hypertension to obtain a possible proxy for high-risk Fontan candidates. METHODS: After electrical preconditioning of the left latissimuss dorsi for 6 weeks in 8 dogs, the right ventricular cavity was totally obliterated with concomittent closure of the tricuspid valve and right pulmonary artery. Modified Fontan circulation was established with the aortic homograft anastomosed between the right atrium and pulmonary trunk, incorporated with a pericardial pouch as a compression chamber (neoright ventricle) fixed onto the epicardial surface of the ventricle. After cardiopulmonary bypass termination, a latissimus dorsi was applied to wrap the pericardial pouch and ventricle clockwise and stimulated with a trained-pulse (25 Hz) at 1:1 synchronization ratio with cardiac beats. RESULTS: Profound right heart failure was noted during Fontan circulation in increased pulmonary vascular resistance (11 +/- 3.2 Wood units), whereas graft pacing showed significant augmentation of systolic pulmonary pressure by 54 +/- 12%, the mean pulmonary flow by 68 +/- 23%, and aortic pressure by 23 +/- 5% at a physiological range of central venous pressure (13.2 +/- 0.7 mmHg). Right heart function curve analysis confirmed marked augmentation of right heart performance, restoring almost normal pulmonary circulation. These functional benefits were sustained up to 4 hours in 4 animals until experiments were terminated. CONCLUSIONS: Dynamic cardiomyoplasty in a modified Fontan procedure is a viable surgical option for univentricular heart, not a Fontan candidate.     

Single lung transplantation in rats with chemically induced pulmonary hypertension.

Physiologic effects of single lung transplantation on pulmonary hypertension were studied in rats with monocrotaline-induced pulmonary hypertension. Inbred rats treated with monocrotaline (40 mg/kg) received a left lung isograft from a normal donor 2 weeks later, when pulmonary hypertension became significant (transplant group; n = 6). These rats and control rats treated with monocrotaline (mediated control group; n = 11) or vehicle alone (normal control group; n = 9) were followed up weekly by metabolic treadmill testing for exercise tolerance and oxygen consumption up to 6 weeks after monocrotaline (4 weeks after transplantation), when all rats underwent hemodynamic and histologic examinations. Whereas maximal oxygen consumption and exercise tolerance consistently deteriorated in the medicated control group of rats, indices in the transplant group stopped deteriorating 2 weeks after lung transplantation and remained at levels similar to those of normal control rats. Severe pulmonary hypertension (68 +/- 19 mm Hg) and right ventricular hypertrophy (right ventricular/left ventricular weight ratio, 0.95 +/- 0.19) were confirmed in medicated control rats in contrast to transplant animals, in which these two indices remained at normal control levels. Whereas left-to-right lung perfusion ratio was constant among rats not receiving transplants (0.69 +/- 0.16), it was significantly elevated (2.27 +/- 0.65; p less than 0.001) in those receiving transplants, suggesting preferential flow through the lung isograft. The results suggest that, in the early phase of pulmonary hypertension, single lung transplantation shifts pulmonary perfusion to the grafted lung, avoiding right ventricular pressure overload and thereby preserving exercise tolerance at a nearly normal level in rats with monocrotaline-induced pulmonary hypertension.     

Characteristics of the beta-adrenergic stimulation of adenylate cyclase activity in rat ventral prostate and its modulation by androgens

Beta-adrenergic agents cause a 2.5-3-fold stimulation of adenylate cyclase activity in rat ventral prostate membrane preparations with an order of potency (KD values) typical of a beta 2-subtype receptor: (-)isoproterenol (20 nM) greater than (-)epinephrine (70 nM) much greater than (-)norepinephrine (1 microM) much greater than dopamine (70 microM). The stimulatory effect exerted by high concentrations of dopamine (greater than 0.1 mM) is completely reversed by propranolol but not by haloperidol or sulpiride, thus indicating an action of dopamine mediated by the beta-adrenergic receptor. One week after castration, basal adenylate cyclase activity in prostatic membranes is 50% reduced. In the same group, the stimulation by isoproterenol is completely abolished in the absence of GTP, while the effect of GTP alone is reduced by 75%. The inhibitory effect of castration on basal as well as isoproterenol- and GTP-stimulated adenylate cyclase activity can be completely reversed by treatment of castrated animals with dihydrotestosterone, thus demonstrating the marked androgen dependency of adenylate cyclase activity in prostatic tissue. Since the response to direct stimulation of adenylate cyclase activity (assessed by NaF and forskolin) is only reduced by 33%-60% while the response to isoproterenol is 100% abolished, the present data indicates that the complete loss of beta-adrenergic responsiveness of prostatic adenylate cyclase following castration includes many steps, including those preceding adenylate cyclase activity, namely the beta-adrenergic receptor itself and/or its coupling via the GTP-binding protein. The large amplitude of the effects observed should facilitate study of the mechanisms involved in the marked regulation of the beta-adrenergic receptor-adenylate cyclase system by androgens in prostatic tissue.     

银杏叶提取物对野百合碱所致肺动脉高压保护作用的实验研究

目的：探讨银杏叶提取物对野百合碱所致肺动脉高压（PAH）的早期保护作用。方法：30只雄性 SD大鼠随机分为3组：对照组、PAH 模型组和治疗组,每组10只。PAH 模型组和治疗组大鼠采用脊背部皮下注射1%野百合碱60 mg/kg的方法复制PAH 模型,注射后第2天开始每日予2 ml 0.9%氯化钠注射液（PAH 模型组）或60 mg/kg银杏叶提取物（治疗组）灌胃;对照组脊背部皮下注射等量溶剂,注射后第2天开始每日予2 ml 0.9%氯化钠注射液灌胃。第22天采用颈外静脉右心导管法测定平均肺动脉压（mPAP）、右心室收缩压（RVSP）,测定右心室、左心室、室间隔的重量,计算右心室肥厚指数（RVHI）;采用 HE染色观察肺细小动脉组织结构情况,并计算直径50~150μm的肺小动脉血管管壁厚度占血管厚度百分比（WA%）和血管管壁面积与血管面积比值（WV%）;采用免疫组化方法观察内皮型一氧化氮合成酶（eNOS）及内皮素-1（ET-1）在大鼠肺组织中的表达情况。结果：PAH 模型组、治疗组的 mPAP、RVSP、RVHI、WA%、WV%与对照组比较均明显升高（P〈0.05）,治疗组的 mPAP、RVSP、WA%、WV%较 PAH 模型组均降低（P〈0.05）,而治疗组与 PAH 模型组的RVHI差异无显著性。免疫组化结果显示,3组 eNOS表达,对照组〉治疗组〉PAH 模型组;3组 ET-1的表达, PAH 模型组〉治疗组〉对照组。结论：银杏叶提取物通过抑制 ET-1的合成、减轻内皮细胞损伤、维持 eNOS的表达,达到减缓PAH 进展的作用。     

盐酸戊乙奎醚对野百合碱致大鼠肺动脉高压的抑制作用

目的探讨盐酸戊乙奎醚是否能够减缓野百合碱导致的大鼠肺动脉高压及是否能够预防或缓解肺血管重构。方法 3~4周龄健康雄性SD大鼠30只,体重90~100g,随机均分为正常对照组(C组)、野百合碱肺高压组(M组)、盐酸戊乙奎醚组(P组),每组10只。M组和P组腹腔注射野百合碱60mg/kg建造大鼠肺动脉高压模型,C组腹腔注射等容量生理盐水。P组大鼠于建模前15min时腹腔注射盐酸戊乙奎醚2mg/kg,建模第2天腹腔注射盐酸戊乙奎醚1mg/kg,C组和M组在相应时点腹腔注射等容量生理盐水,连续使用3周。在建模后第21天,三组大鼠检测血流动力学(肺动脉压、右心室压);处死大鼠前采集静脉血以备血液生化检测:ELISA法检测一氧化氮(NO)含量、内皮素-1(ET-1)含量。处死大鼠后留取左肺组织行病理切片以观察肺组织病理形态学变化,取右肺组织于-80℃冻存以备后续检测。结果 M组和P组右心室SBP、平均肺动脉压、肺动脉SBP和肺动脉DBP明显高于C组(P0.05);P组右心室SBP、平均肺动脉压、肺动脉SBP和肺动脉DBP明显低于M组(P0.05)。M组肺小动脉明显增厚,肺小动脉管腔狭窄甚至闭塞,肺组织炎性细胞浸润非常明显。P组肺小动脉壁增厚减轻,肺组织炎性细胞浸润减轻。M组大鼠血清中NO含量明显低于,ET-1的含量明显高于C组(P0.05);P组大鼠血清中NO含量明显高于M组和C组(P0.05),ET-1含量明显高于C组,但明显低于M组(P0.05)。结论使用野百合碱成功建造了大鼠肺动脉高压模型,NO含量降低、ET-1含量增加可能与野百合碱致大鼠肺动脉高压的形成有关;盐酸戊乙奎醚减缓野百合碱致大鼠肺动脉高压模型的肺动脉压力的升高、改善肺小动脉壁增厚可能与增加NO含量、降低ET-1含量有关。     

Right ventricle-sparing heart transplantation effective against iatrogenic pulmonary hypertension.

BACKGROUND: Right heart failure is the predominant cause of death following heart transplantation, occurring with disturbingly high frequency in patients with severe antecedent pulmonary hypertension. We have recently reported a novel technique of heart transplantation that spares the recipient right ventricle, excising only the recipient left ventricle. The resulting model has 2 right hearts and 1 left heart. The aim is to preserve the recipient's right ventricle, which is already conditioned to pulmonary hypertension. The hope is that, in this way, death due to right heart failure can be prevented in humans. Our prior report was a feasibility study in normal dogs. This study challenges this new technique by creating iatrogenic pulmonary hypertension in the recipient animals. METHODS: Iatrogenic pulmonary hypertension was created in 4 recipient canines by intravenous injection of the pulmonary toxin monocrotaline pyrrole (single bolus of 3.5 to 4.5 mg/kg intravenously [i.v.]). RESULTS: Within 6 weeks of monocrotaline administration, relative pulmonary hypertension occurred (mean pulmonary artery [PA] pressure 20 mm Hg vs 10 mm Hg for controls [p < 0.01]) (pulmonary vascular resistance [PVR] 4.2 vs 1.5 Wood units [P < 0.01]), and right ventricular (RV) hypertrophy developed (RV thickness 11 mm vs 2 mm [P < 0.04]). Histologic examination confirmed severe muscle infiltration and thickening of the media of the pulmonary arterioles. RV-sparing heart transplantation was performed successfully in all 4 animals with pulmonary hypertension. In all cases, the animals were weaned without difficulty from cardiopulmonary bypass, despite the ambient pulmonary hypertension, on low-dose epinephrine, maintaining systolic blood pressure of 104 mm Hg at right atrial pressure of 7 mm Hg. Both right hearts contracted well without dilation or strain. A single "control" traditional orthotopic transplant experiment in an animal with monocrotaline-induced pulmonary hypertension resulted in immediate death from right heart failure. CONCLUSIONS: Right ventricle-sparing heart transplantation ("one-and-one-half heart model") can handle pulmonary hypertension without difficulty. This evidence adds impetus for further pursuing of right ventricle-sparing heart transplantation to decrease the incidence of death from right heart failure in recipients with severe antecedent pulmonary hypertension.     

Beneficial effects of inhaled nitric oxide in adult cardiac surgical patients

BACKGROUND: Pulmonary hypertension with associated right ventricular dysfunction may complicate the postoperative cardiac patient despite maximum pharmacologic and ventilatory support. The purpose of this study was to retrospectively review our experience with inhaled nitric oxide (INO) in adult postoperative cardiac patients with pulmonary hypertension. METHODS: We retrospectively reviewed the medical records of 17 adult cardiac patients treated with INO postoperatively between November 1998 and February 2000. The INO was used to manage pulmonary hypertension postoperatively in patients who had undergone coronary artery bypass graft (CABG) (n = 13), valve operation (n = 3), and combined CABG/aortic valve replacement (n = 1). Hemodynamic and respiratory measurements before INO and again 6 hours after administration were examined. Student's t test was used to analyze the data. RESULTS: Inhaled nitric oxide (20 ppm to 30 ppm) was administered for a median duration of 30.2 hours. The group, as a whole, demonstrated a significant decrease in both mean pulmonary artery pressure and right ventricular stroke work index. In addition, a significant increase in posttherapeutic cardiac index and Pao2/Fio2 ratio was observed. The vasodilatory effects of nitric oxide were specific to the pulmonary circulation as no significant change in mean arterial pressure was noted. Overall mortality was 6%. CONCLUSIONS: Inhaled nitric oxide effectively and selectively lowered right ventricular afterload and right ventricular work in critically ill adult cardiac patients with acute pulmonary hypertension.     

Mechanisms of transplant right ventricular dysfunction.

OBJECTIVE: Right ventricular (RV) dysfunction remains the leading cause of early mortality after cardiac transplantation. The effect of brain death and subsequent hypothermic cardioplegic arrest and storage on subsequent post-transplant right ventricular function was examined. SUMMARY BACKGROUND DATA: Right ventricular dysfunction in the donor heart usually is attributed to failure of the donor right ventricle to adapt to the sudden increase in afterload (pulmonary vascular resistance) in the recipient. Strategies to improve ventricular mechanics in the postoperative period are aimed at reducing pulmonary vascular resistance with vasodilators or augmenting right ventricular contractility with inotropic agents. Events occurring in the donor heart (brain death, hypothermic cardioplegic arrest, and storage) also may be directly related to post-transplant RV dysfunction. METHODS: A canine model of brain death and orthotopic cardiac transplantation was used. A dynamic pressure-volume analysis of RV mechanics was performed using micromanometers and sonomicrometric dimension transducers. Systolic function was assessed by measurement of preload recruitable stroke work (PRSW). Brain death was induced in 17 dogs by inflation of an intracranial balloon. Right ventricular function then was assessed serially to 6 hours (PRSW). Right ventricular adrenergic beta receptor density and function was sampled at control and after 6 hours of brain death. The effect of cardioplegic arrest and hypothermic storage was assessed in a second group of 17 dogs, using the same instrumentation and method of RV analysis. RESULTS: A significant decrease in right ventricular PRSW occurred after brain death, with the average decrease being 37% +/- 10.4% from the control. The RV myocardial beta adrenergic receptor density did not significantly change (253 +/- 34 fmol/ng control vs. 336 +/- 54 fmol/ng after brain death). The adenylyl cyclase activity of the RV beta receptor was assessed and was not altered by brain death. Orthotopic transplantation after cardioplegic arrest and hypothermic storage significantly decreased RV PRSW from 23.6 +/- 2.0 x 10(3) erg to 13.5 +/- 1.4 x 10(3) erg. CONCLUSIONS: These data indicate that the donor right ventricle is exposed to factors significantly detrimental to its mechanical performance well before facing an increased afterload in the recipient. Strategies to reduce RV dysfunction associated with brain death and hypothermic storage could positively impact post-transplant survival.     

Modulation of catecholamine responsiveness and beta-adrenergic receptor/adenylyl cyclase pathway during cardiac allograft rejection1 2

BACKGROUND: This study investigated the changes of catecholamine responsiveness and beta-adrenergic receptor/adenylyl cyclase pathway during acute cardiac transplant rejection. METHODS: Isogeneic Lewis to Lewis and allogeneic Dark Agouti (DA) to Lewis rat cardiac transplants were studied 3 and 5 days after heterotopic intraabdominal transplantation (n=6/group). Myocardial blood flow (MBF), left ventricular systolic pressure (LVSP), maximum pressure development (+dP/dt), and end-diastolic pressure (LVEDP) were measured using an intraventricular balloon. Contractile response to dobutamine (5 microg/kg/min) was also assessed. In separate groups beta-adrenergic receptor density and adenylyl cyclase activity were measured in the grafts, in the recipients' native hearts and in native hearts of sham-operated controls. RESULTS: During mild to moderate rejection cardiac function indices remained unchanged, although MBF and contractile response to dobutamine decreased significantly (P<0.05) in the allogeneic group. The beta-adrenergic receptor density was significantly (P<0.05) increased in both isografts and allografts and in the native hearts of allografted recipients in comparison to native hearts of controls. Adenylyl cyclase activity showed a significant decrease (P<0.05) only in allografts. During severe rejection, LVSP and +dP/dt decreased and LVEDP increased in allografts in comparison to isografts (P<0.05). This was accompanied by a significant decrease in MBF, contractile response to dobutamine, beta-adrenergic receptor density, and adenylyl cyclase activity (P<0.05). CONCLUSIONS: Both microcirculatory disturbances and primary alteration in adenylyl cyclase activity may contribute to decreased contractile reserve in mild to moderate cardiac allograft rejection, whereas beta-adrenergic receptor density seems to be also influenced by cardiac denervation. Severe rejection leads to systolic and diastolic heart failure with complex dysregulation of the beta-adrenergic receptor/adenylyl cyclase pathway and impaired microcirculation.     

Circulatory effects of isoflurane during acute hypercapnia

Acute respiratory acidosis results in increases in cardiac output and in systemic and pulmonary arterial blood pressures. The aim of this investigation was to determine if isoflurane modifies these effects. Nine patients (ASA II or III) scheduled for major surgery took part in the investigation. After the induction of general anesthesia, CO2 was added to the inspiratory gas mixture. After 15 min, ventilation with addition of CO2 (PaCO2 8-9 kPa) isoflurane (3%) was added. Hemodynamic measurements were made to study the effects of acute hypercapnia and the effects of isoflurane during hypercapnia. The addition of carbon dioxide resulted in increases in cardiac output, systemic and pulmonary arterial blood pressures, and right and left ventricular stroke work. The addition of isoflurane during hypercapnia decreased systemic arterial blood pressure, but pulmonary arterial blood pressure was unaffected, cardiac output and stroke volume did not change, and left but not right ventricular stroke work decreased. In conclusion, acute pulmonary hypertension induced by hypercapnia was not affected by isoflurane but, despite increased right ventricular stroke work, there were no signs of right ventricular failure.     

Single lung transplantation in rats with fatal pulmonary hypertension.

Effects of single lung transplantation on fatal pulmonary hypertension were evaluated in rats receiving a lethal dose of monocrotaline. Inbred rats treated with monocrotaline (80 mg/kg) received a left lung isograft at 4 weeks (n = 9) and at 6 weeks (n = 6), when moderate and severe pulmonary hypertension, respectively, had developed. Medicated (n = 12) and nonmedicated rats (n = 12) served as control animals. Each rat was tested weekly with treadmill for exercise tolerance and oxygen consumption during a 10-week period after medication and after they were killed. Medicated control rats lost exercise tolerance and highest oxygen consumption per unit time consistently to the range of resting value (or 45% of nonmedicated control rats), and all died from severe pulmonary vascular occlusive disease with right ventricular hypertrophy before 10 weeks (right ventricular/left ventricular weight ratio of 1.16). All rats receiving a left lung isograft at 4 weeks survived and regained highest oxygen consumption per unit time (87% of nonmedicated control rats), with the lung transplant receiving 65% (nonmedicated control rats, 39%) of cardiac output and milder right ventricular hypertrophy (right ventricular/left ventricular weight ratio of 0.46). Except for one, all rats that received a left lung isograft at 6 weeks tolerated single lung transplantation, but they died soon after reperfusion because of pulmonary edema in the graft that received 58% of cardiac output with right ventricular/left ventricular weight ratio of 0.79. Results of single lung transplantation in rats were dependent on severity of pulmonary hypertension. In rats with moderate pulmonary hypertension, single lung transplantation was successful in reversing exercise intolerance and right ventricular hypertrophy. Single lung transplantation was unsuccessful when pulmonary hypertension was severe in the rat model because increased flow toward the lung transplant resulted in graft pulmonary edema.     

Inhaled nitric oxide decreases pulmonary soluble guanylate cyclase protein levels in 1-month-old lambs

BACKGROUND: Inhaled nitric oxide produces potent pulmonary vasodilation by activating soluble guanylate cyclase and increasing smooth muscle cell concentrations of cyclic guanosine monophosphate. However, responses are often nonsustained, and clinically significant increases in pulmonary vascular resistance have been noted on its acute withdrawal. In vitro and in vivo data suggest that inhaled nitric oxide decreases endogenous nitric oxide synthase activity. The effects of inhaled nitric oxide on the downstream mediators of the nitric oxide/cyclic guanosine monophosphate cascade, soluble guanylate cyclase and phosphodiesterase 5, have not been investigated. We sought to determine the effects of inhaled nitric oxide on endogenous cyclic guanosine monophosphate levels, soluble guanylate cyclase, and phosphodiesterase 5 protein levels in the intact lamb. METHODS: Eleven 1-month-old lambs were mechanically ventilated. In 7 lambs, inhaled nitric oxide (40 ppm) was administered for 24 hours and then acutely withdrawn. Intermittent lung biopsy samples were obtained for cyclic guanosine monophosphate concentrations and soluble guanylate cyclase and phosphodiesterase 5 protein levels (Western blot analysis). RESULTS: Initiation of nitric oxide decreased left pulmonary vascular resistance by 26.2%, and withdrawal rapidly increased pulmonary vascular resistance by 77.8% (P <.05). Tissue cyclic guanosine monophosphate concentrations initially increased during nitric oxide therapy but were not maintained during the 24-hour exposure. In addition, cyclic guanosine monophosphate concentrations rapidly decreased after nitric oxide withdrawal (P <.05). The alpha soluble guanylate cyclase (-45.7%) and beta soluble guanylate cyclase (-48.4%) protein levels decreased during nitric oxide therapy (P <.05), whereas phosphodiesterase 5 proteins levels were unchanged. CONCLUSIONS: These data suggest a role for decreased soluble guanylate cyclase and its resulting decrease in cyclic guanosine monophosphate concentrations in the nonsustained response to nitric oxide and the rebound pulmonary hypertension noted on its acute withdrawal. Phosphodiesterase 5 inhibitors may be a useful adjunct therapy during inhaled nitric oxide to preserve cyclic guanosine monophosphate levels and thereby preserve nitric oxide responsiveness and prevent rebound pulmonary hypertension.