Extracorporeal Membrane Oxygenation (ECMO): An Option for Cardiac Reccovery from Advanced Cardiogenic Shock.

Mechanical circulatory support can prevent multi-organ failure and death in patients with advanced cardiogenic shock. Here we describe our experience using extracorporeal membrane oxygenation (ECMO) for treatment of advanced cardiogenic shock which has been used by our team for daily routine care in more than 200 patients during the last five years at the Penn State Medical Center. Venoarterial (VA) ECMO has been used as a viable therapeutic option for advanced cardiogenic shock as a bridge to recovery (BTR) or bridge to next decision (BTD). Our group performed a retrospective review of data from 155 patients from our single center cohort treated with VA ECMO for advanced cardiogenic shock. After successful ECMO treatment, the one year survival rate of patients with ischemic heart disease was 73.7 %, and the one year survival for patients with non-ischemic heart disease was 75%.

Pump Thrombosis following HeartMate II Left Ventricular Assist Device Implantation in a Patient with Aspirin and Plavix Resistance.

Despite advances in pump technology, thromboembolic events and pump thrombosis are potentially life-threatening complications in patients with continuous flow ventricular assist devices. Here we describe a patient with pump thrombosis following LVAD HeartMate II implantation presenting with Aspirin and Plavix resistance and signs of acute hemolysis as manifested by high LDH, changing pump power, pulse index and reduced pump flows.

Managing heart failure with immunomodulatory agents.

The evidence in favor of immune activation as an operative mechanism that contributes to the progression of heart failure continues to accumulate. Indeed, a number of clinical trials have demonstrated the clinical interest of interventions in this area for many years, but none have proven useful. The only trial ever conducted to define the effect of immunotherapy in mortality, however, is the one currently ongoing using Etanercept in patients with symptomatic heart failure. Irrespective of the final outcome of the study, the growing interest in inflammation as a contributory pathway in disease progression has now opened the field to develop new strategies for intervention. Whether specific or non-specific therapies may prove useful will be defined only by the results of randomized clinical trials.

Cardiac hypertrophy after transplantation is associated with persistent expression of tumor necrosis factor-alpha.

BACKGROUND: The mechanisms that contribute to cardiac allograft hypertrophy are not known; however, the rapid progression and severity of hypertrophy suggest that nonhemodynamic factors may play a contributory role. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine produced in cardiac allografts and capable of producing hypertrophy and fibrosis; therefore, we suggest that TNF-alpha may play a contributory role. Accordingly, the aims of our study were to define the role of systemic hypertension in the development of hypertrophy, characterize the histological determinants of hypertrophy, and characterize the expression of myocardial TNF-alpha after heart transplantation. METHODS AND RESULTS: To separate the effect of hypertension from immune injury in the development of cardiac allograft hypertrophy, we measured the gain in left ventricular mass by 2D echocardiography in heart transplant recipients and lung transplant recipients who developed similar rates of systemic hypertension. The gain in left ventricular mass was 73% in heart transplant recipients and 7% in lung transplant recipients (P<0.0001). By comparing myocardial samples obtained during the first week after transplant and at 1 year, we found that there was a significant increase in total collagen content (P<0.0001), collagen I (P<0.0001), collagen III (P<0.0001), and myocyte size (P<0.0001). These changes were associated with persistent myocardial TNF-alpha expression. CONCLUSIONS: We suggest that the contribution of hypertension to cardiac allograft hypertrophy is minimal and that persistent intracardiac expression of TNF-alpha may contribute to the development of cardiac allograft hypertrophy.

Influence of cytoimmunological state on the development of tuberculosis in heart transplant recipients.

We examined the relationship between the development of tuberculosis and the cytoimmunological state of orthotopic heart transplant (HTx) recipients, which is affected by immunosuppressive therapy. Tuberculosis developed in 7 (1%) of 716 HTx recipients (four men and three women, aged 33-71 years) during a 7-year period, the standardized annualizing rate being about 1370/100000 per year, which is greater than the 17.5/100000 per year in the general population of Germany. Tuberculosis developed in the early posttransplant period in four patients when they were experiencing episodes of ongoing rejection, after 2.5, 3.5, 4.0, and 9.0 months, respectively, the standardized annualizing rate being 780/100000 per year. In three of those four patients, cytoimmunological monitoring was carried out until the development of tuberculosis. The repeated administration of pulsed corticosteroid therapy followed by oral steroids reduced T-cell and CD4+ T-cell counts, which could have increased the risk of tuberculosis developing if they were exposed. The cytoimmunological state of the remaining three patients in whom tuberculosis developed late after HTx, when episodes of ongoing rejection did not exist, was similar to the preoperative state, the standardized annualizing rate being 590/100000 per year. These findings indicate that the relatively high incidence of tuberculosis in post-HTx patients could be attributable to the immunosuppressive therapy given, including steroids.

Outcome of heart transplantation in patients previously infected with hepatitis C virus.

The lack of knowledge about the course of hepatitis C virus infection (HCV) before heart transplantation (HTx) prompted us to describe our experience with 4 such patients who presented with positive HCV serology before surgery. Two experienced non-liver related deaths at 3.5 and 5 years after HTx, and none of the patients developed signs of hepatic insufficiency during the follow-up (mean 3.8 years). Tests for HCV antibodies were frequently negative, whereas viral RNA was detected in 81% of the measurements, showing that virus detection techniques seem to be more sensitive than serology techniques in detecting HCV infection in this group of patients. Although immunosuppression promotes active HCV replication, it does not seem to change the chronic features of HCV infection during the first years in patients with good liver function.

New strategies for the management of acute decompensated heart failure.

Acute heart failure in adults is the unfolding of heart failure in minutes, hours or a few days. Low output heart failure describes a form of heart failure in which the heart pumps blood at a rate at rest or with exertion that is below the physiological range and the metabolizing tissues extract their required oxygen from blood at a lower rate, causing a proportionately smaller oxygen amount remaining in the blood. Therefore, a widened arterial-venous oxygen difference occurs. High output heart failure is characterized by pumping blood with a rate above the physiological range at rest or during exertion, resulting in an arterial-venous oxygen difference, which is normal or low. This may be caused by peripheral vasodilatation during sepsis or thyrotoxicosis, blood shunting, or reduced blood oxygen content/viscosity (Fig. 1). The differentiation between low output heart failure versus high output heart failure is of highest importance for the choice of therapy and therefore the information and the monitoring of the systemic vascular resistance. Patients who present with acute heart failure suffer from a severe complication of different cardiac disorders. Most often they have an acute injury that affects their myocardial performance (eg, myocardial infarction) or valvular/chamber integrity (mitral regurgitation, ventricular septal rupture), which leads to an acute rise in left-ventricular filling pressures resulting in pulmonary edema.

[Neurological form of onset in haemophagocytic lymphohistiocytosis]. / Forma de debut neurológico de la linfohistiocitosis hemofagocítica.

INTRODUCTION: Haemophagocyte lymphohistiocytosis (HLH) is a hematological disorder, autosomal recessive and in which there is benign proliferation of histiocytes with intense phagocytic activity of hematopoietic cells. The clinical features include fever, pancytopenia, coagulation disorders, liver dysfunction, the presence of histiocytes and haemophagocytes in the bone marrow, lymph nodes, spleen and liver. The nervous system is always involved and sooner or later patients develop a nervous system disorder with variable symptoms which may include irritability, disorders of consciousness, convulsions, ataxia, nystagmus or signs of intracranial hypertension. CLINICAL CASE: Onset of the disease showing purely neurological features is rare. We therefore describe the case of an 8 month old baby with HLH with a purely neurological condition involving irritability, horizontal rapid eye movements and vertical saccadic movements of both eyes and focal convulsive seizures. Initial complementary examinations were normal, except for study of the CSF with a lowered protein level and cells (monocytes). Finding hepatosplenomegaly and pallor, together with the laboratory investigations, made it advisable to do a bone marrow punch biopsy to detect haemophagocytes which would be diagnostic of HLH. In spite of chemotherapy there was rapid neurological deterioration, with alterations of the white matter and hydrocephaly which required insertion of a ventriculo-peritoneal shunt. The patient died when he was 10 months old. CONCLUSIONS: The cases of HLH in which cerebromeningeal disorders alone precede systemic symptoms are extremely rare. Hence the interest in reporting this case, so that it may be borne in mind in other cases of acute neurological onset. In this case initially there was encephalitis alone, but this was rapidly followed by systemic complications.

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.

Right ventricular diastolic function in beta-thalassemia major: echocardiographic and clinical correlates.

BACKGROUND: Cardiac hemochromatosis remains the most frequent cause of death in beta-thalassemia major. Previous studies suggest an important right ventricular (RV) contribution to cardiac morbidity and mortality. Studies with Doppler echocardiography have shown contradictory results regarding left ventricular (LV) filling, whereas the RV filling characteristics have not been studied yet. We prospectively studied the pattern of RV filling and investigated echocardiographic and clinical correlates during baseline and follow-up examinations in patients with beta-thalassemia major. METHODS AND RESULTS: The study included 79 patients, aged 24.2 +/- 8.0 years, with homozygous beta-thalassemia major without symptoms of heart failure with normal LV function and 51 healthy control subjects, matched for age, sex, and body surface area. Doppler echocardiographic indexes of systolic and diastolic ventricular function were assessed. Hemodynamic measurements were obtained in 8 patients by right heart catheterization. An abnormal RV relaxation pattern was evident in the patient group. The LV filling characteristics indicated increased preload without abnormal alteration, whereas catheterization findings were consistent with a high cardiac output state. Short tricuspid deceleration time (DT) had the best predictive value for subsequent cardiac events. Repeat echocardiographic study in 35 asymptomatic patients at 19 +/- 7 months demonstrated deterioration of LV systolic function, chamber enlargement, and shortening of DT of tricuspid and mitral inflow. CONCLUSIONS: In patients with homozygous beta-thalassemia major without cardiac disease, the pattern of RV filling is abnormally altered, indicating impaired relaxation. In contrast, the LV filling is compatible with increased preload, as in chronic anemia. Short DT of early tricuspid inflow carries important prognostic value. LV remodeling occurs over time along with transition toward a restrictive ventricular filling pattern.

Forma de debut neurológico de la linfohistiocitosis hemofagocítica / Neurological form of onset in haemophagocytic lymphohistiocytosis

Introducción. La linfohistiocitosis hemofagocítica (LHH) es una enfermedad hematológica, autosómica recesiva, en la que se produce una proliferación benigna de histiocitos con intensa actividad fagocítica de células hematopoyéticas. Cursa con fiebre, pancitopenia, trastornos de la coagulación, disfunción hepática, presencia de histiocitos y hemofagocitos en médula ósea, nódulos linfáticos, bazo e hígado. El compromiso del sistema nervioso es constante y todos los pacientes desarrollan más tarde o más temprano un cuadro neurológico que puede manifestarse con síntomas variables como irritabilidad, trastornos de conciencia, convulsiones, ataxia, nistagmo o signos de hipertensión intracraneal. Caso clínico. El debut de la enfermedad con un cuadro exclusivamente neurológico es poco común y por ello presentamos la observación de un lactante de 8 meses con LHH que presenta un cuadro exclusivamente neurológico, en forma de irritabilidad y movimientos oculares rápidos horizontales y sacádicos verticales de ambos ojos y crisis convulsivas focales. Los exámenes complementarios iniciales fueron normales, excepto el estudio del LCR que reveló hiperproteinorraquia y celularidad (monocitos). La evidencia de sustancia blanca con áreas de edema, necrosis y atrofia cortical [1,3,5]. una hepatoesplenomegalia y palidez, junto a la analítica, aconsejó practicar una punción biopsia de médula ósea que detectó hemofagocitos, diagnóstico de LHH. A pesar del tratamiento quimioterápico se produjo un rápido deterioro neurológico, con alteraciones en la sustancia blanca y acompañado de hidrocefalia que requirió derivación ventriculoperitoneal. El paciente falleció a los 10 meses. Conclusión. Los casos de LHH en los que el compromiso cerebromeníngeo exclusivo precede a los síntomas sistémicos es extremadamente raro, de aquí el interés en comunicarlo y tenerlo en cuenta frente a un paciente con una clínica neurológica aguda, en este caso exclusivamente de encefalitis pero que se complicó rápidamente con manifestaciones sistémicas (AU)

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.

Pre-existing elevated pulmonary vascular resistance: long-term hemodynamic follow-up and outcome of recipients after orthotopic heart transplantation.

BACKGROUND: Elevation of pulmonary vascular resistance (PVR) has been considered to predict a bad outcome after orthotopic heart transplantation (HTx). A transpulmonary gradient (TG) > or =15 mmHg and PVR > or =5 wood (w) are correlated with a three-fold increase in 2-days as well as 30-days and 6-, 12-month mortality. METHODS: We performed a retrospective analysis of 400 consecutive transplanted patients (pts) on hemodynamic data over a time period of 3.5 years. In 83 pts (23%) preoperative PVR was > or =5 w and TG >15 mmHg. Vasodilator studies were performed in this group of pts in order to evaluate pulmonary vasoreactivity or hemodynamic improvement. RESULTS: Hemodynamic follow-up post-transplantation showed a significant (p<0.001) decrease in mean TG to 8.8 mmHg within the first, 7.7 after the fifth year as well as decrease in PVR from 5.5 to 1.6, within the first and fifth year post-transplantation. Compared to the control group (n=286) (re-transplants n=6 and pediatric pts n=25 excluded) pts with TG <15 mmHg and/or PVR <5 w, transplanted within the same period, 30-day mortality and cumulative survival after 1 and 5 years do not show any significant difference with a mortality of 3%, 22% and 33% (p<0.05). Subgroup analysis for pts with endstage of ischemic versus dilatative cardiomyopathy has not shown any significant difference in mortality. CONCLUSIONS: In a retrospective analysis of 400 pts elevated PVR does not predict a bad outcome after orthotopic heart transplantation in early and late mortality.

Chronic urticaria serum induces histamine release, leukotriene production, and basophil CD63 surface expression--inhibitory effects ofanti-inflammatory drugs.

BACKGROUND: A role of potential histamine-releasing autoantibodies against the high-affinity IgE receptor on the surface of basophils and mast cells is discussed in the pathogenesis of chronic urticaria. This so-called autoimmune urticaria may be diagnosed by a positive intracutaneous autologous serum skin test, which is found in about 30% of patients with chronic urticaria. OBJECTIVE: Our purpose was, first, to compare the effect of complement-inactivated sera of 20 patients with chronic urticaria and positive autologous serum skin tests, 20 patients with chronic urticaria and negative skin tests, and 20 control subjects without chronic urticaria (10 atopic and 10 nonatopic subjects) and, second, to analyze the effect of anti-inflammatory drugs on the serum activity. METHODS: The following assay systems were used: release of histamine in whole blood samples, surface expression of the activation marker CD63 on basophils, and sulfidoleukotriene de novo production in leukocyte suspensions. Whole blood, basophils, and leukocyte suspensions were obtained from a nonatopic and an atopic donor. RESULTS: Sera of patients with autologous serum skin test positive chronic urticaria resulted not only in significantly increased histamine release compared with skin test-negative chronic urticaria sera but also in a significant higher induction of basophil CD63 surface expression and sulfidoleukotriene de novo production. However, serum activity was neither characteristic for chronic urticaria nor for chronic urticaria with a positive autologous serum skin test. Preincubation with dapsone, chloroquine, and lidocaine dose dependently resulted in a significant reduction of all histamine release, CD63 expression, and sulfidoleukotriene production. In addition, mizolastine was able to inhibit serum-induced sulfidoleukotriene production. CONCLUSION: Further studies investigating the in vivo effect of these drugs will have to clarify their role in the management of the subset of patients with chronic urticaria demonstrating serum-induced inflammatory effects.

Influence of different assist devices on survival after orthotopic heart transplantation.

BACKGROUND: In 1995, a risk factor of 1.88 was indicated for one-year mortality in connection with bridging to heart transplantation. Both one-year and three-year survival rates in patients bridged to transplantation were less than 80%. METHODS: From 3/89 to 12/98, 903 orthotopic heart transplantations were performed at our center in 888 recipients. Bridging was necessary in 142 patients. RESULTS: The one-year survival rate was 76% in pts without VAD, 86% in pts bridged with VAD and 66% in pts with VAD due to postcardiotomy syndrome. The three-year survival rates were 73%, 80% and 55% respectively. CONCLUSIONS: Early and late results in patients bridged to transplantation remarkably improved over 1995. One-year and long-term survival rates are significantly lower when assist devices are used in patients with postcardiotomy syndrome. Despite a high incidence of assist-related complications, electively bridged patients showed significantly better early and long-term results than the control group.

Myocardial gene expression of regulators of myocyte apoptosis and myocyte calcium homeostasis during hemodynamic unloading by ventricular assist devices in patients with end-stage heart failure.

BACKGROUND: In patients with end-stage heart failure, characterized by an increased susceptibility to cardiomyocyte apoptosis and a labile cardiomyocyte calcium homeostasis, a ventricular assist device (VAD) is implanted for bridging to cardiac transplantation and results in myocardial unloading. Although phenotype changes in the failing heart are assumed to result from hemodynamic overload, the reversibility of these changes under unloading is unknown. METHODS AND RESULTS: By use of quantitative reverse-transcription polymerase chain reaction, mRNA expression analyses were performed on left ventricular specimens obtained from 10 nonfailing donor hearts (from 8 patients with dilated cardiomyopathy and 2 patients with coronary heart disease) at the time of VAD implantation and 36 to 169 days later during VAD removal with subsequent cardiac transplantation. In terminally failing hearts before VAD support, left ventricular mRNA analyses revealed increased Pro-ANP, reduced antiapoptotic Bcl-x(L) and antiapoptotic Fas isoform FasExo6Del, and a decreased ratio of sarcoplasmic reticulum Ca(2+)-ATPase per sarcolemmal Na(+)-Ca(2+) exchanger in comparison with nonfailing ventricles. After VAD unloading, ventricular transcription of Pro-ANP was immediately normalized, and apoptotic DNA fragmentation was attenuated. In patients with dilated cardiomyopathy, mRNAs of Bcl-x(L) and FasExo6Del/Fas were enhanced depending on time on VAD. The Bcl-x(L) mRNA level correlated positively with that of the Bcl-x(L) protein. Transcription of sarcoplasmic reticulum Ca(2+)-ATPase/Na(+)-Ca(2+) exchanger demonstrated recovery in only 4 of 10 patients. CONCLUSIONS: Mechanical support of the failing heart induces a time-dependent change in myocardial gene expression compatible with a decreased susceptibility to apoptosis.