Cardiac endothelin-like immunoreactivity and preproendothelin-1 mRNA expression in human heart failure

Endothelin (ET) induces hypertrophy of cardiomyocytes and increases synthesis of collagen in vitro. Interestingly, these features are hallmarks of the cardiac remodeling taking place in heart failure. The aim of the present study was to examine cardiac ET peptide and preproET-1 mRNA synthesis in human heart failure. Cardiac tissue was obtained from 11 patients with end-stage heart failure undergoing orthothopic heart transplantation (NYHA III-IV). Cardiac tissue from nine organ donors served as controls. The specimens were examined by immunohistochemistry and mRNA slot blot analyses. Significantly stronger ET-1-like immunoreactivity (ET-1-ir) was seen in the left atrial myocardium of failing hearts compared to the left atrial myocardium of donor hearts. Within each heart, the epicardium showed the strongest ET-1-ir. Left ventricular preproET-1 mRNA expression in the entire group of patients did not differ significantly from that of donor hearts. However, hypertrophic obstructive cardiomyopathy may be associated with a twofold increase in left ventricular preproET-1 mRNA. We report an increase in cardiac ET peptide in human heart failure.     

Effect of acute brain death on release of atrium and B-type natriuretic peptides in an animal model

INTRODUCTION: Atrium and B-type natriuretic peptides (ANP and BNP) and big endothelin (ET)-1 are markers for severity of heart failure and may be used in the quality assessment of donor hearts. Elevated cardiac troponins predict early graft failure after heart transplantation. This study evaluated the effects of acute brain death (BD) on the release of ANP, BNP, big ET-1, and cardiac troponins in an animal model. MATERIALS AND METHODS: Pigs were randomized into a BD group (n=5) and a control group (n=5). In the first group, acute BD was induced, and anesthesia was stopped. In the control animals, a sham operation was performed, and anesthesia was continued. Parameters were measured at baseline and for 13 hours postoperatively. RESULTS: After acute BD, there were significant hemodynamic changes. In the control group, the BNP level was higher than in the BD group and decreased over time (P =0.016). There was no significant change in BNP release in the BD group up to 13 hours (P =0.1). ANP release remained stable over time in the control group (P =0.35) but decreased in the BD group (P =0.043). The big ET-1 levels were not different between groups. Cardiac troponin I was elevated in the BD group 5 hours after BD (P< 0.05) but remained under 1.5 mg/L throughout the study. CONCLUSION: Acute BD did not lead to an increase of BNP and ANP levels. Moreover, intact brain function seems to augment the release of natriuretic peptides from the myocardium. Further clinical evaluation of prognostic values of natriuretic peptides for the assessment of donor hearts is necessary. Cardiac troponins are a useful additional tool in the evaluation of donor hearts.     

Sequentially paced heterotopic heart transplant in the left chest provides improved circulatory support for the failed left ventricle. A potential biologic bridge to orthotopic transplantation

Acute experimental transplantation of an allograft heart in a heterotopic position was performed in 14 sheep. The donor heart was implanted in the left side of the chest with left atrial, aortic, and pulmonary artery anastomoses. Hemodynamic studies were performed to evaluate the physiologic effects of the procedure, particularly when recipient left ventricular failure was produced by inflow and outflow obstruction. Pacing techniques were developed and tested to coordinate the rhythm of the two hearts either synchronously or sequentially with variable intervals between depolarization of the two hearts. Hemodynamic studies were performed to evaluate the rhythm that would most optimize the physiology. The cardiac index remained essentially unchanged when the dominant circulatory support was shifted from recipient left ventricle to donor left ventricle by producing recipient left ventricular failure (3.79 +/- 0.6 to 3.30 +/- 0.8, p = no significant difference). Consistent and reliable paced rhythms were achieved in each case. The cardiac index was significantly higher when the hearts were paced sequentially rather than synchronously (3.76 +/- 0.5 versus 3.29 +/- 0.5, p less than 0.04). Allograft donor hearts small in size or slightly inadequate otherwise, which may be unsuitable for orthotopic heart transplantation, may still be used heterotopically for short-term support. Their use would maximize the use of all donor organs and the survival of patients awaiting a suitable organ. Further, it may also be possible to use sequentially paced xenografts heterotopically for short-term left ventricular assistance as a bridge to orthotopic heart transplantation.     

The Comparison of Mitogen-Activated Protein Kinases That Become Activated Within the Left Ventricular and Right Atrial Tissues Following Heart Transplantation in Canine Model

The activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in ischemia/reperfusion injury. Some reports have documented MAPKs activation of the myocardium in human models, using right atrial (RA) tissue for samples. This study compared the activation of MAPKs in left ventricle (LV) and RA tissues in canine heart transplantation. Four dogs were used as baseline data at two points, before and 20 min after warm ischemia (baseline model), and eight dogs (four pairs of donor and recipient) were used at other points: 4 h after cold ischemia, and at 10, 60, and 180 min after reperfusion (transplantation model). In the transplantation model, donor hearts were left in situ for 20 min after cardiac arrest, and were immersed in Celsior solution for 4 h after coronary flushing. Orthotopic heart transplantation was then performed. Two groups were created: the LV and RA groups (n = 4 in each group). Heart tissue was harvested from the left ventricular wall in the LV group and from the right atrial appendage in the RA group. The activation of MAPKs, including p38 MAPK, c-Jun N-terminal protein kinase (JNK), and extracellular signal-regulated protein kinase (ERK), was evaluated at each point. The activation patterns of p38 MAPK and ERK were similar in the RA and LV groups, but JNK activation was different in the two groups, after ischemia and reperfusion. Thus, RA tissue may be deliberately used as a substitute for LV tissue when investigating the activation of MAPKs in a human model.     

Gene transfection of hepatocyte growth factor attenuates reperfusion injury in the heart

Background. Hepatocyte growth factor (HGF), a ligand for the c-Met receptor tyrosine kinase, plays a role as organotrophic factor for regeneration of various organs. HGF has an angiogenic activity and exhibits a potent antiapoptotic activity in several types of cells. Although HGF and the c-Met/HGF receptor are expressed in the heart, the role of HGF in the heart has remained unknown.

Methods. After we analyzed changes in expression of endogenous HGF and c-Met mRNA levels in the rat left ventricle after myocardial infarction, the human HGF gene in hemagglutinating virus of Japan (HVJ)-liposome was transfected into the normal whole rat heart. Three days after transfection, the heart was subjected to global warm ischemia and subsequent reperfusion, followed by assessment of its cardiac functions.

Results. Both HGF and c-Met/HGF receptor mRNAs were expressed in adult rat heart, and c-Met/HGF receptor mRNA was upregulated in response to myocardial infarction. HGF-transfected heart showed significant increase of human HGF protein level in the heart. Cardiac functions in terms of the left ventricular developed pressure, maximum dp/dt, and pressure rate product in hearts with HGF gene transfection were significantly superior to those in control hearts. In addition, leakage of creatine phosphokinase in the coronary artery effluent in hearts with HGF gene transfection was significantly lower than that in control hearts.

Conclusions. These data indicated that both HGF and c-Met/HGF receptor mRNAs were upregulated in response to myocardial ischemic injury, and that HGF is likely to have a cytoprotective effect on cardiac tissue, presumably through the c-Met/HGF receptor.     

Alterations in alpha adrenoreceptor density and localization after mechanical left ventricular unloading with the Jarvik flowmaker left ventricular assist device.

Cardiac alpha one adrenoreceptors (alpha(1)AR) are known to mediate positive inotropism in human ventricular myocardium. In the early stages of heart failure, ventricular contractility is maintained by adrenergic stimulation, rennin-angiotensin activation, and other neurohormonal and cytokine system responses. As the disease progresses, however, these compensatory mechanisms cease to provide benefit; ventricular dilation and fibrosis occur and cardiac function deteriorates. When ventricular contractility becomes severely depressed and is no longer responsive to inotropic support, insertion of a left ventricular assist device (LVAD) may allow the left ventricle to rest, remodel, and recover some contractile function. Our previous work has demonstrated that the myocardium has the capacity to repair itself during a period of unloading, after which some patients are able to resume a normal lifestyle and no longer need a cardiac transplant.     

Apoptotic Markers in Donor Hearts After Brain Death vs Circulatory Death

BackgroundUse of donation after circulatory death (DCD) hearts is becoming more prevalent in cardiac transplantation. However, there is no standardized approach to myocardial preservation, and little data exists on ultrastructural changes in DCD hearts. We have previously identified increased proapoptotic and proinflammatory activity in brain dead donor (BDD) hearts that subsequently exhibit primary graft failure and lower levels in DCD left atrial tissue. This study further investigates these markers and correlates them with cardiac function in DCD hearts.MethodsThis prospective study used donor hearts deemed unsuitable for transplant after gaining institutional ethics approval; 11 human hearts were obtained from 5 DCD donors and 6 BDDs. All hearts were preserved by continuous microperfusion for 4 hours with a cold crystalloid solution and then were evaluated on a blood perfusion bench rig. After 4 hours perfusion and working assessment, tissues from all cardiac chambers were stored for later messenger RNA (mRNA) analysis for proapoptotic and proinflammatory markers.ResultsSignificantly raised levels of caspase-1, BNIP3, and NADPH oxidase mRNA expression were identified in cardiac chambers from BDD hearts compared to DCD hearts, and these differences were exaggerated in older donors. In the pooled analysis, lower expression of caspase-1, NF-κB1, and BNIP3 mRNA correlated with developed pressure at 1 hour after reperfusion in the right ventricle, but not the left.ConclusionCompared to BDD hearts, DCD hearts exhibit less stimulation of proapoptotic cascades and reactive oxygen species, potentially reducing their susceptibility to ischemic reperfusion injury.     

The comparison of mitogen-activated protein kinases that become activated within the left ventricular and right atrial tissues following heart transplantation in canine model.

The activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in ischemia/reperfusion injury. Some reports have documented MAPKs activation of the myocardium in human models, using right atrial (RA) tissue for samples. This study compared the activation of MAPKs in left ventricle (LV) and RA tissues in canine heart transplantation. Four dogs were used as baseline data at two points, before and 20 min after warm ischemia (baseline model), and eight dogs (four pairs of donor and recipient) were used at other points: 4 h after cold ischemia, and at 10, 60, and 180 min after reperfusion (transplantation model). In the transplantation model, donor hearts were left in situ for 20 min after cardiac arrest, and were immersed in Celsior solution for 4 h after coronary flushing. Orthotopic heart transplantation was then performed. Two groups were created: the LV and RA groups (n = 4 in each group). Heart tissue was harvested from the left ventricular wall in the LV group and from the right atrial appendage in the RA group. The activation of MAPKs, including p38 MAPK, c-Jun N-terminal protein kinase (JNK), and extracellular signal-regulated protein kinase (ERK), was evaluated at each point. The activation patterns of p38 MAPK and ERK were similar in the RA and LV groups, but JNK activation was different in the two groups, after ischemia and reperfusion. Thus, RA tissue may be deliberately used as a substitute for LV tissue when investigating the activation of MAPKs in a human model.     

Analysis of the distribution of histologic myocardial lesions during acute cardiac rejection. Experimental study in rodents.

BACKGROUND AND METHOD: Asymmetric distribution of histologic lesions have been reported in grafted hearts that could hamper the interpretation of right ventricular endomyocardial biopsy. Heterotopic heart transplantations were performed in rats (n=59) and guinea pigs (n=20). Grafted hearts were examined by a pathologist who established the degree of cardiac rejection in the four cardiac cavities. RESULTS: Forty cardiac rejections were diagnosed in rats and ten in guinea pigs. An asymmetric distribution of histologic lesions was observed in 34 (68%) rejected hearts with greater lesions in the auricular myocardium than in the ventricular myocardium (n=25, 50%). One (n=18) or two degrees (n=7) differentiated the severity of rejection between atria and ventricles. Cardiac rejection score was significantly greater in atria than in ventricles (3.12+/-0.18 vs. 2.6+/-0.2 (P<0.01) in rats and 2.35+/-0.37 vs. 1.6+/-0.47 (P<0.001) in guinea pigs. There were histologic lesions of rejection in the auricular myocardium in seven cases, although the ventricular myocardium was completely normal. In nine (18 %) other grafted hearts the degree of rejection was equal in the auricular myocardium and ventricular septum but was greater than the degree of rejection noted in the right and left ventricular free walls. CONCLUSION: The distribution of histologic lesions of acute cardiac rejection in rodents was heterogeneous in grafted hearts which exhibited greater lesions in the atria than in ventricles. This should be taken into consideration in the evaluation of new methods of detection of cardiac rejection and in the diagnosis of acute cardiac rejection in humans.     

Heart and liver transplantation. Consistent survival after prolonged donor heart preservation.

Twelve dogs underwent orthotopic cardiac transplantation after donor heart preservation for 24 hr in a hypothermic hypertonic intracellular solution. Donors were divided into two groups: continuous oxygenated perfusion and nonperfusion. After 24 hr, transplantation was performed. All six perfused and four nonperfused donors hearts survived a 24-hr postoperative period. Survivors had normal cardiac output, right and left atrial pressures, and aortic pressures. After transplantation, all perfused hearts demonstrated mild left ventricular damage while nonperfused hearts had severe damage. Hypothermic hypertonic intracellular perfusion may allow improved protection for short-term myocardial preservation and survival after extended myocardial preservation.     

Mechanical unloading and cell therapy have a synergistic role in the recovery and regeneration of the failing heart

The problem of a growing patient population with end-stage heart failure and a fixed cardiac donor pool has stimulated the development of novel therapies for heart failure. Two therapeutic strategies have emerged with the potential to improve the landscape of the clinical management of heart failure. First, left ventricular assist device therapy is able to sustain the circulation of patients in end-stage heart failure and may promote cardiac recovery. Secondly, stem cell therapy can potentially be used to induce myocardial regeneration replacing lost or non-functioning native myocardium. In this review, we present evidence that these strategies may overlap significantly in their mechanisms of action at the systems, organ, tissue and cellular levels. We review the current clinical evidence of their combined use.     

Heart transplantation in perspective

Heart disease remains one of the leading causes of death in the western world. In the 35 years since the first human heart transplants, cardiac transplantation has become established as the therapeutic option of choice in the management of terminal cardiac failure. Since 1981, the introduction of cyclosporin for immunosuppression has dramatically increased cardiac transplantation. However, several obstacles limit further utilization, including limited availability of donor hearts, limited ischemic time tolerated by donor hearts, and chronic rejection. Research is underway into donor heart preservation and new immunosuppressant drugs in an effort to increase donor organ availability. Due to these constraints, alternative therapies are under development. More than 2,000 circulatory assist devices have been implanted with >25% used as a bridge to heart transplantation. The University of Ottawa Heart Institute began the first Canadian implantation of circulatory assist devices in 1986 and has implanted 23 total artificial hearts and 23 ventricular assist devices. The Heart Institute is also developing a totally implantable electrohydraulic ventricular assist device (EVAD) for long-term mechanical support outside the hospital. Another alternative being evaluated for clinical use is xenotransplantation. The major obstacle for widespread use of clinical xenotransplantation remains graft rejection, and fundamental research is ongoing to address hyperacute and delayed xenograft rejection. While cardiac transplantation is the most effective treatment of terminal heart failure, limited donor hearts compel us to rely on alternatives. In the future, the research underway on xenotransplantation and mechanical circulatory assist devices will provide new options for the clinical treatment of terminal cardiac failure.     

心脏手术病人心肌组织心钠素含量的测定

为探讨心脏手术病人心肌组织心钠素含量变化与心脏病的关系。应用放射免疫分析方法对３７例心脏手术病人心肌组织心钠素的含量进行测定。结果风湿性心脏病病人心肌组织心钠素含量明显高于先天性房、室间隔缺损者。证实心功能不同，心肌组织心钠素含量不同，在病理状态下，心室亦分泌心钠素。