Some aspects of experimental heart transplantation

In 144 experiments carried out on dogs, the possibility was proved to use for the recipient's protection during transplantation either deep immersion hypothermia or total artificial circulation without it being filled with the donor's blood. In order to maintain cardiac activity after clinical death of a non-heparinized organism for the purpose of later heart transplantation the authors propose to use the direct mechanical cardiac massage (DMCM) which makes possible not only to restore adequate pulsating blood flow in the dead body but also to assess after restoration of the heart's pump function the suitability of using it for transplantation. Functional adaptation of a transplanted heart proceeds in 3 stages: pronounced heart failure (5-15 min), functional heart failure (4-6 hours), stabilization of cardiac activity (2-3 days). Implantation of a second heart in experimental left ventricular failure of the recipient helped to achieve an effective and prolonged reduction of excessive functional overload of the affected heart.     

Assessment of myocardial viability by dobutamine stress echocardiography in patients with ischemic heart disease

Detection of viable (hibernating) myocardium is necessary for determination of prognosis and tactics of treatment of patients with ischemic heart disease. For detection of viable myocardium and investigation of possibilities of its restoration 60 patients with ischemic heart disease (54 men, mean age 52+/-8 years) were examined before coronary artery bypass grafting or coronary angioplasty. Presence of viable myocardium was characteristic for patients with multivessel coronary artery disease (83%) with stenoses >90%, with well developed collateral circulation (81%). Sustained restoration of contractility of hibernating segments for 1 year after revascularization was noted in 70% of cases. Dobutamine stress echocardiography was found to have high diagnostic potential for detection of viable myocardium.     

Viability of the myocardium after twenty-four-hour heart conservation--a preliminary study

BACKGROUND: Orthotopic heart transplantation following ischemic times beyond four hours is associated with increased risk of early graft failure. The use of modern myocardial preservation strategies could enable safe transplantation after long-term conservation. In this study, we tested a new myocardial protection regime in an experimental model of 24 h storage. METHODS: Orthotopic heart transplantations (n=15) were performed in a pig model. Donor hearts were flushed with Bretschneider solution, excised, and stored for 24 hours at 4 degrees C. During implantation, controlled reperfusions with substrate-enriched leukocyte-depleted blood cardioplegia were performed after each anastomosis. Blood cardioplegia contained 1 mmol/l of the Na(+)-H(+)-exchange inhibitor HOE 642 and 100 mg/l of adenosine. Controlled reperfusion was continued with leukocyte-depleted blood for 20 min. A microaxial pump was inserted after heart transplantation and circulatory assistance was maintained for five hours to prevent right heart failure. RESULTS: No initial graft failure could be observed. Thirteen hearts could be weaned from extracorporeal circulation. Due to bleeding problems, kidney and lung failure only five hearts could be included in the final analysis. Hemodynamics of these hearts remained stable with epinephrine at 0.1 micro g/kg/min. Myocardial oxygen consumption 20 min after start of reperfusion (5.3+/-2.0 ml/100 g/min) did not differ significantly versus baseline (6.8+/-2.0 ml/100 g/min). Oxygen extraction six hours after heart transplantation was also well preserved compared to baseline (58.0+/-10.2 versus 49.2+/-8.8 %). Histological examination six hours after transplantation using luxol fast blue staining revealed that only 1.0 % of the myocytes were irreversibly damaged. CONCLUSIONS: The data indicate full viability of the myocardium after 24 h conservation. The preservation technique described could contribute to the extension of conservation times in heart transplantation and enable transplantation of marginal donor hearts.     

Role of cardiac surgery in the post-myocardial infarction patient with heart failure

Limited donor availability for orthotopic cardiac transplantation has led surgeons to develop surgical alternatives to treat congestive heart failure as a result of ischemic cardiomyopathy. Coronary revascularization plays a clear role in patients with ischemic cardiomyopathy, substantial viable myocardium subtended by coronary stenoses, and presence of anginal symptoms. It is unclear whether patients with heart failure symptoms but no angina benefit from bypass surgery. Some of these patients present with left ventricular dilatation and akinetic/dyskinetic scars, and are therefore candidates for surgical ventricular restoration. Current evidence is lacking as to whether ventricular reconstruction should be performed along with coronary revascularization. Functional mitral regurgitation is often seen in patients with end-stage cardiomyopathy, and its presence portends decreased survival. Mitral valve repair has been shown to improve quality of life, functional class, and to contribute to left ventricle reverse remodeling; however, it has been insufficient in improving survival.     

Cell- and gene therapy for ischemic heart disease

Despite advances in pharmacological therapies, cardiovascular surgery, use of mechanical assist devices, and organ transplantation, more than half of the patients with clinically evident heart failure die within 5 years of the initial diagnosis. The use of cellular cardiomyoplasty and gene therapy offer a promising approach for both the prevention and treatment of heart failure. This review will discuss the current state of these emerging fields and the prospects of introducing the methods into clinical practice. Since functional restoration of the damaged heart presents a formidable challenge, developing strategies for the prevention of post-infarct heart failure remains of utmost priority. New strategies to optimize cell delivery, homing and survival on the one side and safe and efficient application of gene therapy to the failing myocardium on the other side are indispensable in order to achieve myocardial recovery after acute infarction or chronic ischemic damage.     

Transplantation of an oversized heart.

In response to the limited number of available donors, the criteria for accepting hearts have been expanded. In a 46-year-old female (160 cm, 56 kg) with a body surface area (BSA) of 1.58 m(2), an orthotopic heart transplantation was performed. She received the heart from a 34-year-old male donor (190 cm, 90 kg, BSA 2.58 m(2)). During transplantation, the obvious difference between the donor's heart and the recipient's pericardium did not cause a technical problem. However, the postoperative course was characterized by severe circulation problems. Due to a hemodynamically significant right heart impression, a consecutive pericardectomy had to be performed. After excision of the left and the right side of the pericardium, the patient returned to a stable condition. The consecutive course was without cardiopulmonary problems and the patient was discharged from the hospital 20 days later. The last twelve-month follow-up showed good cardiac function and excellent physical condition. We conclude that an oversized donor heart can be used for heart transplantation as long as the pericardium is left open and a left and right pericardectomy is performed.     

Total artificial heart bridging: a temporary support for deteriorating heart transplantation-candidates--methods and results

Since 1975 at the 2. Dept. of Surgery, University of Vienna, Austria, artificial circulation devices and artificial hearts have been constructed and in experimental use. We started a clinical heart transplantation (HTX) program in 1984, and up to now more than 40 HTXs have been performed. Since May 1986, 3 patients--all suffering from end stage dilatative cardiomyopathy--received total artificial heart (TAH) as a temporary support until HTX was possible. Two of them were transplanted after 9 and 10 days. The third patient, who additionally suffered from a postinfarctial lung abscess and had to undergo an indispensable lobectomy contemporary with TAH implantation, could not be transplanted due to an incurable infection, which he died of after 22 days on TAH. The temporary TAH implantation proved to be a valuable measure preventing life-threatening circulatory deterioration. After restoration of a sufficient circulation by the implanted system, the patients' general conditions improved and the concomitant dysfunctions of kidneys, brain, and other vital organs, due to cardiogenic shock, could be rectified in those two patients, who underwent transplantation. Thromboembolic complications were observed only in the third patient, who developed a small infarction in the anterior lobe of the left hemisphere caused by cerebral embolism after 3 weeks of TAH pumping. The use of TAH is liable to severe, even lethal, complications. At present it should be used only as a last resort. If a donor heart is not available, this measure can be a real chance to save the patient's life.     

Heterotopic heart transplantation in three patients at the Texas Heart Institute

Seventy-three orthotopic and three heterotopic transplantations have been done in our institution, and in this report, we describe the procedure and outcome of those who underwent heterotopic transplantation. Three patients were in critical condition while awaiting donors for heart transplantation, and in each case, a suitable donor could not be found. Smaller donor hearts became available, and knowing that these patients would die without some kind of immediate action, we performed heterotopic heart transplantations. Patient Number 1 was a 53-year-old diabetic man who was in the last stages of heart disease when a small donor heart became available. Because of his rapidly deteriorating condition, we did a heterotopic transplantation. The patient is presently well and functioning normally. Patient Number 2 was a 26-year-old woman who received the heart of a 13-year-old donor after it became obvious that she could not wait for a suitable donor. We performed a heterotopic transplantation, after which the patient continues to function well. Patient Number 3 was a 53-year-old man who weighed 260 lbs. When a suitable donor could not be found, the heart of a 170-lb man became available and was used in a heterotopic transplantation. This patient also continues to be active and well. After considering the various advantages and disadvantages of heterotopic transplantation, we are convinced that there is a definite place for this procedure in some patients with end-stage cardiac failure, although we still believe that orthotopic transplantation should be offered to most recipients.     

Status of permanent cardiac replacement for end-stage congestive heart failure

Permanent replacement of the heart in patients with end-stage congestive heart failure has long been sought after as the most definitive solution to an ever-growing problem. While cardiac transplantation is an effective therapy for many patients with end-stage congestive heart failure, this potential has been limited by the donor organ shortage and other limitations of long-term survival inherent in cardiac transplantation. While research anddevelopment of the total artificial heart continues to be of considerable interest, present-day mechanical circulatory support most commonly involves the use of left ventricular assist devices as a bridge to transplantation. Pneumatic and electromechanical pumps are now commonly employed in modern transplant practices with excellent hemodynamic function. The TCI HeartMate left ventricular assist device is now approved by the Food and Drug Administration for clinical implantation, with excellent preliminary results. Advances in the area of temporary and extended mechanical circulatory support are crucial to the ultimate development of a totally implantable artificial heart.     

Interim cardiac replacement with a mechanical heart: staged cardiac transplantation

Lack of donor heart availability complicates the management of terminally ill patients who are candidates for cardiac replacement. The total artificial heart has been used as a bridge to transplantation in three patients with terminal cardiomyopathy. Acute allograft rejection and the lack of another donor heart prompted us to use the mechanical heart as a bridge to re-transplantation in a 33-year-old man. The cardiac prosthesis functioned well for 11 hours, when a second transplantation was performed, but the patient died of right heart failure 48 hours after the second transplantation. Critical factors in such cases include (1) a prompt decision to proceed with cardiac replacement; (2) avoidance of long periods of cardiopulmonary bypass; (3) prosthetic device availability; and (4) surgical team preparedness, with technical expertise in transplantation, allograft explantation, and total artificial heart implantation/explantation, with re-transplantation.     

The response of the failing heart to chronic mechanical unloading

PURPOSE OF REVIEW: The authors present a comprehensive analysis of the evidence in support of improvements at the cellular, structural, and hemodynamic levels after left ventricular assist device support. RECENT FINDINGS: The use of left ventricular assist devices as a strategy to bridge patients to cardiac transplantation and, more recently, as a form of destination therapy has provided a great opportunity to study failing myocardium at various time points. Specifically, myocardial samples can be obtained from patients at the time of left ventricular assist device implantation and again at explant, thereby allowing comparisons between paired samples of failing myocardium obtained before and after mechanical unloading. SUMMARY: A body of knowledge has been generated that illustrates the ability of the myocardium to "heal." This information may give us better insight into cellular and molecular mechanisms of heart failure and potential new therapies for patients with end-stage heart failure.     

Influence of ACE-inhibition and mechanical unloading on the regulation of extracellular matrix proteins in the myocardium of heart transplantation candidates bridged by ventricular assist devices

BACKGROUND: Whether adverse structural changes in the myocardium due to remodelling can be reversed by ventricular assist device (VAD) support in patients with end-stage heart failure is controversial. AIMS: To investigate the effect of VAD support on the extra-cellular matrix. METHODS: We analysed the collagen content in terminal failing ventricles of VAD-patients and donor hearts using 4-hydroxyproline for total collagen and real time RT-PCR for fibronectin (FN), collagen I alpha 1 (Col1A1), III alpha 1 (Col3A1) and TGF beta 1 analysis. RESULTS: Compared to donor hearts we found similar increases in Col1A1 and TGF beta1 but not Col3A1 and FN mRNAs, which were similar in the myocardium from patients receiving a VAD or heart transplant. However, patients receiving ACE-I during VAD-support had lower Col1A1 mRNA content at transplantation. The total collagen content was not influenced by mechanical unloading or by ACE-I medication. CONCLUSION: Mechanical unloading by VAD does not reduce the collagen content of the terminal failing ventricle possibly due to increased TGF beta1 levels. However, Col1A1 production may be reduced by ACE-I medication during VAD support.     

Transplantation of the heart in an infant and an adult

Experience with human heart transplantation is reported. A technically successful infant heart transplantation was performed on December 6, 1967. The child died 61/2 hours postoperatively in severe metabolic and respiratory acidosis.

Another heart transplantation was performed on January 5, 1968; the recipient was a 57-year old man. The donor heart was unable to support the circulation, and the patient died 101/2 hours postoperatively.

Problems in the selection of donors and of recipients, in the surgical technic, and in the postoperative management are discussed.     

心室辅助装置对改善终末期心力衰竭患者心功能的作用

目的 通过对心力衰竭患心室辅助装置置入前,后及撤除前、后心功能参数的分析,了解长期机械循环支持对终末期心力衰竭病人心功能改善,心肌损伤修复的影响。方法 用超声对机械心室辅助时间３０￣７９５天的２２例患术前,术后,装置撤除前,后左室射血分数（ＬＶＥＦ）,左室舒张末内径（ＬＶＥＤＤ）、左室收缩末内径（ＬＶＥＳＤ）进行测定,将结果进行对比分析。结果 心室辅助装置置入前,后ＬＶＥＦ,ＬＶＥＤＤ,ＬＶＥ     

Indications for heart transplantation in congenital heart disease

In this review we have looked at indications for cardiac transplantation in congenital heart disease. An outline of the general principles of the use of transplant as a management strategy both as a first line treatment and following other surgical interventions is discussed. We explore the importance of the timing of patient referral and the evaluations undertaken, and how the results of these may vary between patients with congenital heart disease and patients with other causes of end-stage heart failure. The potential complications associated with patients with congenital heart disease need to be both anticipated and managed appropriately by an experienced team. Timing of transplantation in congenital heart disease is difficult to standardize as the group of patients is heterogeneous. We discuss the role and limitations of investigations such as BNP, 6 minute walk, metabolic exercise testing and self estimated physical functioning. We also discuss the suitability for listing. It is clear that congenital heart patients should not be considered to be at uniform high risk of death at transplant. Morbidity varies greatly in the congenital patient population with the failing Fontan circulation having a far higher risk than a failing Mustard circulation. However the underlying issue of imbalance between donor organ supply and demand needs to be addressed as transplant teams are finding themselves in the increasingly difficult situation of supporting growing numbers of patients with a diverse range of pathologies with declining numbers of donor organs.     

Granulocyte-colony stimulating factor increases donor mesenchymal stem cells in bone marrow and their mobilization into peripheral circulation but does not repair dystrophic heart after bone marrow transplantation

BACKGROUND: Hereditary disordered cardiac muscle could be replaced with intact cardiomyocytes derived from genetically intact bone marrow (BM)-derived stem cells. METHODS AND RESULTS: Cardiomyopathic mice with targeted mutation of delta-sarcoglycan gene underwent intra-BM-BM transplantation (IBM-BMT) from transgenic mice expressing green fluorescence protein. The host BM and the peripheral blood were completely reconstituted by donor-derived hematopoietic cells by IBM-BMT. Treatment with granulocyte-colony stimulating factor (G-CSF) markedly increased donor-derived mesenchymal stem cells (MSC) in the BM and their mobilization into the peripheral blood after IBM-BMT. Treatment with isoproterenol (iso) for 7 days caused myocardial damage and left ventricular (LV) dysfunction in the cardiomyopathic mice. Co-treatment with iso and G-CSF increased donor BM cell recruitment to the heart and temporarily improved LV function in the cardiomyopathic mice with or without IBM-BMT. However, the cardiac muscle was not replaced with donor BM-derived cardiomyocytes in the cardiomyopathic mice with or without IBM-BMT, and this was associated with no improvement of LV function of mice aged 20 weeks. CONCLUSIONS: These results suggest that G-CSF enhances engraftment of donor MSC in the BM and their mobilization into the peripheral circulation after IBM-BMT but MSC recruited to the heart do not differentiate into cardiomyocytes and do not repair the dystrophic heart.     

Alternative therapies for orthotopic heart transplantation

Heart failure has reached epidemic proportions in the United States. More than 5 million patients are treated for heart failure and approximately a half a million new patients are diagnosed with this disease each year in the United States. Recent pharmacological therapies have been used for the treatment of this patient population, but heart failure remains a major source of morbidity and mortality for patients. Orthotopic heart transplantation is a viable treatment option for heart failure patients; however, cardiac transplantation is limited by the donor availability. Limited donor organ availability has led to the development of alternative therapeutic strategies, including xenotransplantation, mechanical support devices, and cell transfer/tissue engineering protocols. This review highlights the current treatment modalities and emerging strategies for the treatment of advanced heart failure.     

重症慢型克山病的治疗-心脏移植(附3例报告)

目的探讨心脏移植对治疗重症慢型克山病的治疗效果。方法对三例重症慢型克山病患者分别行标准术式、全心脏原位移植术、双腔原位心脏移植。移植术中供心保护采用经冠状静脉窦逆行灌注氧合血。术前后系统护理、抗感染、抗排斥反应和对症处理。结果移植吻合时间分别为６５分、７７分和８２分。术后前２例恢复顺利,无并发症。第３例术后右心功能不全,经系统治疗,术后５天好转,２周后出现肺感染系统抗炎后痊愈;术后３个月出现糖尿病,胰岛素治疗后得到控制。３例患者已分别存活近５年、４年余和１年余,心功能均为Ｉ级。结论认为心脏移植是治疗重症慢型克山病的有效措施之一,良好的供心保护、确切的吻合技术、合理应用免疫抑制剂、及时防治术后并发症是提高移植近、远期疗效的重要因素     

Cardiomyopathy and heart transplantation in children

Cardiomyopathy is one of the most common causes of death in children with heart disease. Increasingly, dilated cardiomyopathy is recognized to be familial, and specific gene products related to the myocyte cytoskeleton and contractile proteins have been identified. Other associations with metabolic disease, dysmorphic syndromes, and neuromuscular disease are important to establish, particularly in pediatric patients, to guide therapy and patient selection for transplantation. Survival in children with dilated cardiomyopathy depends on accurate diagnosis and aggressive therapy. Patients may respond to conventional treatment for heart failure or may deteriorate, requiring mechanical support. Extracorporeal membrane oxygenation has been used effectively for mechanical support in children until improvement occurs or as a bridge to transplantation. For those who are listed, the mortality rate while waiting for a donor organ averages approximately 20%. Survival after transplantation is good, with an intermediate survival rate of approximately 70%. Late survival remains to be determined in the current cyclosporin era but may in fact be improving. However, increased organ donation or strategies to increase the size of the organ donor pool, such as xenotransplantation, are needed to significantly reduce the rate of mortality while waiting.