Michael M. Koerner

Regression of fibrosis and hypertrophy in failing myocardium following mechanical circulatory support.

BACKGROUND The cellular and structural changes that occur during long-term ventricular unloading leading to cardiac recovery are poorly understood. However, we have previously demonstrated that left ventricular assist device (LVAD) support leads to a significant decrease in intracardiac tumor necrosis factor-alpha (TNF-alpha), a protein capable of producing hypertrophy and fibrosis. METHODS To further define the beneficial effects of long-term ventricular unloading on cardiac function, we determined the effect of mechanical circulatory support on fibrosis and hypertrophy in paired myocardial samples of 18 patients with end-stage cardiomyopathy obtained at the time of LVAD implantation and removal. RESULTS We determined total collagen as well as collagen I and III by a semiquantitative analysis of positive immune-stained areas in pre- and post-LVAD myocardial samples. We found that total collagen content was reduced by 72% (p < 0.001), whereas collagen I content decreased by 66% (p < 0.001) and collagen III content was reduced by 62% (p < 0.001). Next, we determined myocyte size by direct analysis of cellular dimensions utilizing a computerized edge detection system in pre- and post-LVAD myocardial samples. We found that myocyte size decreased in all patients studied for an average reduction of 26% (33.1 +/- 1.32 to 24.4 +/- 1.64 microm, p < 0.001). CONCLUSION These data demonstrate that long-term mechanical circulatory support significantly reduces collagen content and decreases myocyte size. We suggest that the reduction of fibrosis and hypertrophy observed may in part contribute to the recovery of cardiac function associated with long-term mechanical circulatory support.

Evidence of improved right ventricular structure after LVAD support in patients with end-stage cardiomyopathy.

BACKGROUND Although many reports demonstrate the hemodynamic benefits of left ventricular assist devices (LVAD) in right-sided circulation, it is not known whether the right ventricular myocardium goes through reverse remodeling after left ventricular mechanical circulatory support. Accordingly, the purposes of our studies were 1). to investigate the right ventricular changes that occur in fibrosis, in cellular hypertrophy, and in intra-myocardial tumor necrosis factor alpha (TNF-alpha) levels in patients receiving LVAD support; and 2). to determine whether the type of LVAD used influences right ventricular myocardial changes. METHODS AND RESULTS We measured myocyte size, total collagen content, and TNF-alpha levels using semi-quantitative immunohistochemical analysis of myocardial samples from the right and left ventricles of control and failing myocardia, either supported by 1 of 2 distinct forms of LVADs or without support. We found that when compared with control, although myocyte size was not increased in the right ventricle of failing myocardia (p = not significant), total collagen content and myocardial TNF-alpha levels were decreased in the right ventricle compared with controls (p < 0.01 and p < 0.001, respectively). CONCLUSION These data demonstrate that chronic left ventricular unloading with either pulsatile or continuous-flow devices decreases right ventricular total collagen and myocardial TNF-alpha content. We suggest that the decreased fibrosis and normalization of cytokine milieu observed may in part contribute to the recovery of right-sided cardiac function associated with chronic mechanical circulatory support.

Extended donor criteria: use of cardiac allografts after carbon monoxide poisoning.

BACKGROUND An increasing demand for cardiac allografts for the treatment of end-stage cardiac failure has led to a shift in the traditional views about donor criteria. The use of allografts exposed to high concentrations of carbon monoxide is still under discussion. The current literature on this topic is contradictory. We describe our experience with orthotopic cardiac transplantation, using cardiac allografts after carbon monoxide poisoning. METHODS Between March 13, 1989 and August 1, 1996, 770 orthotopic heart transplantations were performed in our center. Within this period, we accepted five cardiac allografts from brain-dead, carbon monoxide-poisoned donors. Donor history showed carbon monoxide intoxication in all cases. At the time of organ explantation, donor hemodynamic parameters were feeble in all patients. RESULTS The postoperative course was uneventful in three of the five recipients. The overall 3-year survival rate in this small group is 40%. Induction therapy or rescue therapy with mono/polyclonal antibodies was not necessary. Myocardial right-ventricular biopsies did not show any specific signs of carbon monoxide poisoning. CONCLUSIONS In our opinion, cardiac allografts from donors exposed to carbon monoxide can be transplanted successfully in infants and adults, if there are no signs of severe hemodynamic dysfunction in the presence of a normal central venous pressure and low-dose support with catecholamines and there are no electrocardiographic changes in combination with elevated transaminase. With extended donor criteria, the hearts of carbon monoxide-poisoned victims could increase the number of suitable organs and lower the death rate of patients on the United Network for Organ Sharing and Eurotransplant International Foundation waiting lists.

MECHANICAL CIRCULATORY SUPPORT AFTER ORTHOTOPIC HEART TRANSPLANTATION

Frequently the only therapy for primary graft- and right heart failure, as well as low output syndrome from acute of chronic rejection, is implantation of a mechanical circulatory support system, until recompensation or retransplantation. At our institution, mechanical assist devices were implanted in 25 heart recipients for a cute rejection (n=9), primary graft failure (n=7), acute right heart failure (n=7), and chronic rejection with low output syndrome (n=2). Patients (pts) with primary graft failure (n=3) received an intraaortic balloon pump (IABP), one pt an IABP plus Abiomed®-System for left ventricular support, one pt the Thoratec®-System for biventricular support. Patients with right heart failure (RHF) received the Biomedicus® centrifugal pump for right ventricular support. Nine pts suffered from acute rejection. Six pts received an IABP, one the Biomedicus® as femoro-femoral bypass, one the Abiomed®-System for biventricular support, two the Thoratec®-System for biventricular support and two within this group switched from the Biomedicus® pump to the Thoratec®-System for biventricular support. Patients with chronic graft failure (n=2) received the Novacor®-System (LVAD) for left ventricular support, one received a Tojobo®-System and an oxygenator for biventricular support post coronary artery bypass surgery. Support time ranged from 0.5-h to 73 days. Five pts were weaned. Two (8%) of 25 pts were retransplanted, 18 (72%) died in spite of mechanical support from multiple organ failure. The use of a mechanical assist device after heart transplantation is encouraging only in the case of early right heart failure, as well as primary and chronic graft failure. In view of the poor results, the use of mechanical assist devices should not be recommended in the case of heart failure caused by acute rejection.

Extended Donor Criteria: Hemodynamic Follow-up of Heart Transplant Recipients Receiving a Cardiac Allograft from Donors ≥60 Years of Age1

BACKGROUND Heart transplantation (HT) has become a therapeutic option for patients suffering from endstage heart failure. The increasing demand for cardiac allografts has led to a shift toward extended donor criteria. In a retrospective analysis of 859 HT recipients, we report on the hemodynamic outcome of 19 HT patients who received cardiac allografts from donors > or =60 years of age. METHODS From March 1989 to December 1997, we performed 883 orthotopic HT in 74 children and 809 adults at our transplant center. Within this period, 19 patients (17 women and 2 men) received cardiac allografts from donors > or =60 years of age. Recipient age ranged from 57 to 78 years (mean, 65+/-5 years). RESULTS HT could be performed successfully in 19 cases. The early mortality rate was 16% (n=3). The late mortality rate was 37% (n=7). All long-term survivors are stable at New York Heart Association classification II (New York Heart Association Class II = resting hemodynamics: cardiac output normal; left ventricular end diastolic filling pressure elevated; clinically not compromised during mild to moderate workout). Although only 19 patients were retrospectively evaluated, there was a statistically significant (P<0.05) difference in survival among patients who received organs from male (11 vs. 8*) compared with female (8 vs. 2*) (*=death) donors. CONCLUSION In our experience, it is possible to increase the cardiac donor pool by accepting allografts from donors, preferably female, > or =60 years of age in selected cases without a coronary angiogram, if hemodynamic parameters are in a normal range on mild-to-moderate inotropic support. We do not recommend cardiac allografts from donors > or =60 if there are signs of coronary insufficiency in the electrocardiogram, if left ventricle filling pressures are above normal on mild-to-moderate inotropic support and optimum hemodynamic management, or if there are signs of segmental dysfunction or mitral insufficiency >I in the echocardiogram.

Heart transplantation for end‐stage heart failure caused by iron overload

Few reports exist concerning heart transplantation in recipients with end‐stage myocardiopathy‐associated heart failure caused by iron overload occurring with β‐thalassaemia, Diamond‐Blackfan syndrome or haemochromatosis. Seven potential transplant candidates (six male, one female, mean age 26 years) with such heart failure, following desferrioxamine application subcutaneously over a number of years, and intravenously during their hospitalization before transplantation, were retrospectively analysed. Five were New York Heart Association (NYHA) class IV, three experienced one or more resuscitations immediately before transplantation could be performed. Continuous, high‐volume, veno‐venous haemofiltration was necessary in two patients. One of these two candidates additionally had to be bridged, first with a right ventricular, then with a biventricular assist device. Five of the seven patients survived, two with haemochromatosis, one with β‐thalassaemia major and one with Diamond‐Blackfan syndrome following transplantation. One non‐transplanted candidate with β‐thalassaemia major has been recompensated for 5 years. Survival was 14–74 months. Our results demonstrate the feasibility and indication of transplantation in patients with such heart failure and the satisfying outcome of immunosuppression is described.

Assist devices for circulatory support in therapy-refractory acute heart failure.

Purpose of review Acute cardiogenic shock has a high mortality. The number of mechanical circulatory assist devices to encounter this life-threatening condition is steadily growing. These devices enable physicians to treat patients with acute cardiac failure refractory to conventional therapy. Mechanical circulatory assist devices are considered last resort to prevent or to reverse a cardiogenic shock. Different centrifugal, pulsatile or nonpulsatile (axial) flow pumps are available to rescue patients in different scenarios. These mechanical circulatory assist devices can be placed percutaneously or surgically as extracorporeal or intracorporeal mechanical circulatory assist devices. Recent findings Percutaneous mechanical circulatory assist devices are useful to establish rapid life-saving circulatory support under different circumstances. A stabilized patient can then be transferred to an intensive care unit, a catheterization laboratory or an operating room for further assessment and additional treatment with possible change to a mid-term or long-term mechanical circulatory assist device. Summary Percutaneous mechanical circulatory assist devices can be implanted in an emergency setting in patients with acute cardiogenic shock refractory to conventional therapy irrespective of the given location. The choice for a specific mechanical circulatory assist device should be based on the underlying condition and individualized prognosis. Based on the findings of this review, circulatory or axial-flow pumps should be considered first-line devices.

Hemodynamic follow-up of cardiac allografts from poisoned donors.

BACKGROUND The current shortage of donor organs, combined with an increasing demand for cardiac allografts, means that extended donor criteria are becoming more and more accepted. The use of cardiac allografts for transplantation from donors after acute poisoning is still under discussion; few data are currently available in the medical literature. We describe our experience with 19 orthotopic heart transplant recipients of organs from donors after acute intoxication with different agents. METHODS Between March 1989 and December 1997, 883 orthotopic heart transplantations were performed at our transplant unit. Within this group, we accepted donor hearts after ethanol intoxication (n=1), benzodiazepine (n=1), alkylphosphate (E 605) in combination with beta-blocker intoxication (n=1), carbon monoxide poisoning (n=5), digitalis (n=1), digitalis/glibenclamide (n=1), chlormethiazole (n=1), propoxyphene (n=1), alkylphosphate (E 605) (n=1), insulin (n=2), neprobamate/ thiocyacide/flurazepam (n=1), paracetamol (n=1), carbamazepine (n=1), and cyanide (n=1) intoxication. At the time of organ explantation, hemodynamic data were available from all patients. RESULTS Early mortality in this group was 11%; cumulative survival after 5 years was 74%. CONCLUSIONS Based on our limited experience, cardiac allografts from donors exposed to different kinds of poisons can be transplanted in selected cases. If the donor organ is not hemodynamically compromised, showing regular filling pressures on low or mild inotropic support just before explantation, and if there are no electrocardiographic changes in combination with elevation of the transaminases, cardiac allograft transplantation seems to be a safe and life-saving procedure.

Cardiac transplantation: the final therapeutic option for the treatment of heart failure.

End-stage heart failure is still associated with a decrease in quality and prognosis of life. Cardiac transplantation remains the final extraordinary therapeutic option for the treatment of truly irreversible end-stage heart failure in all age groups. The selection process of candidates and the acceptance of patients with relative contra-indications is characterized by the experience and skills of an interdisciplinary transplant team, which should have access to different mechanical circulatory support systems for short-term or long-term use: bridging to transplant as well as for recovery.

Cardiac allograft vasculopathy: advances in diagnosis.

Cardiac allograft vasculopathy (CAV), characterized by diffuse intimal thickening and luminal narrowing in the arteries of the allograft, is the leading cause of morbidity and mortality in cardiac transplant recipients. Many transplant centers perform routine annual surveillance coronary angiography. However, angiography can underdiagnose or miss CAV due to its diffuse nature. Intravascular ultrasound (IVUS) is more sensitive than angiography. IVUS provides not only accurate information on lumen size, but also quantification of intimal thickening, vessel wall morphology, and composition. IVUS has evolved as a valuable adjunct to angiography and the optimal diagnostic tool for early detection. Noninvasive testing such as dobutamine stress echocardiography and nuclear stress test have shown considerable accuracy in diagnosing significant CAV. Computed tomographic imaging and cardiac magnetic resonance imaging are promising new modalities but require further study. This article reviews the diagnostic methods that are currently available.