A fatal case of Human Herpesvirus 6 chronic myocarditis in an immunocompetent adult

Background

Human Herpesvirus 6 (HHV-6) is an important cause of fulminant or acute viral myocarditis in immunocompromised or immunocompetent patients. However the physiopathological mechanisms of HHV-6 related acute myocarditis and the involvement of subsequent HHV-6 reactivation phases in the development of chronic cardiomyopathies remain to be assessed.

Objectives

To describe a case of fatal HHV-6 chronic myocarditis in an immunocompetent adult.

Study design

Case report and detailed histological and viral diagnoses by combination of histology/immunohistochemistry and polymerase chain reaction techniques on cardiac tissues.

Results

Histopathological analysis of ventricular tissues showed large interstitial and scarring fibrotic areas with a moderate mononuclear cell infiltrate compatible with histological aspect of chronic myocarditis. Detection of both HHV-6 by real-time PCR and viral glycoproteins in mononuclear and endothelial cells by immunohistochemistry evidenced an ongoing cardiac HHV-6 replication with viral late protein synthesis activity.

Conclusions

This case report indicates that HHV-6 can establish a chronic active myocarditis leading to heart failure in immunocompetent subjects.     

Acute fulminant myocarditis in children and adolescents: the role of mechanical circulatory assist

We report children and adolescents in fulminant myocarditis undergoing prolonged circulatory support with different assist devices. Between 1994 and 2004, seven children and adolescents (aged 7-18 years, mean age 13.5 years) were treated with VADs (5 Thoratec, 1 Medos, 1 Novacor) for circulatory support. Three patients underwent left ventricular support; biventricular support was necessary in four patients. Four patients (three left VADs, one bi-VAD) could be successfully bridged to heart transplantation after a mean support time of 163 days (56-258 days). One 7-year-old girl (Medos-BVAD) died after a support time of 11 days because of irreversible multiorgan failure. One 18-year-old patient was successfully weaned from Thoratec BVAD after 66 days with complete recovery of left ventricular function. As good markers, atrial and brain natriuretic peptides were found which reached normal values after recovery of myocardial function. A 15-year-old girl is still on the device. In children or adolescents with irreversible shock in fulminant myocarditis with an anticipated mortality of 100%, both successful bridging to heart transplantation and successful bridging to recovery are possible. Young patients with fulminant myocarditis should be rapidly transferred to a clinic with a mechanical circulatory support program to offer this life-saving option.     

Results of extracorporeal life support implementation in routine clinical practice: single center experience

Aim

To describe our experience in the clinical application of extracorporeal life support (ECLS) and analyze whether ECLS leads to acceptable clinical outcomes in patients with cardiac failure.

Methods

Data from clinical database of University Hospital Center Zagreb, Croatia, on 75 patients undergoing ECLS support from 2009 to 2014 due to cardiac failure were retrospectively analyzed. Outcomes were defined as procedural and clinical outcomes. ECLS as a primary procedure and ECLS as a postcardiotomy procedure due to inability to wean from cardiopulmonary bypass were analyzed.

Results

ECLS was used in 75 adult patients, and in 24 (32%) of those procedural success was noted. ECLS was implemented as a primary procedure in 36 patients and as a postcardiotomy procedure in 39 patients. Nine out of 39 (23.08%) patients had postcardiotomy ECLS after heart transplantation. Bleeding complications occurred in 30 (40%) patients, both in primary (11/36 patients) and postcardiotomy group (19/39 patients). ECLS was established by peripheral approach in 46 patients and by central cannulation in 27 patients. In 2 patients, combined cannulation was performed, with an inflow cannula placed into the right atrium and an outflow cannula placed into the femoral artery. Eleven patients treated with peripheral approach had ischemic complications.

Conclusion

ECLS is a useful tool in the treatment of patients with refractory cardiac failure and its results are encouraging in patients who otherwise have an unfavorable prognosis. The idea of extracorporeal life support (ECLS) became a reality with the introduction of the heart-lung machine by Gibbon in 1954 (1). However, only in 1971 the first successful extracorporeal membrane oxygenation treatment was described (2). Since then continuous technological improvements have led to the growing interest in this type of treatment (3).ECLS may significantly improve the level of patient care in patients with acute and chronic heart failure. It is an advanced form of treatment and the patient management is carried out by a multidisciplinary team of cardiac surgeons, anesthesiologists, and cardiologists.There are two main groups of indications for ECLS: those not related and those related to cardiac surgery. Primary ECLS procedures are not related to cardiac surgery but to acute cardiorespiratory failure arising from underlying cardiac disease. Postcardiotomy ECLS procedures may be considered as a secondary procedure and are directly related to cardiac surgery procedures. These procedures are indicated after cardiac surgery procedures when patients cannot be weaned from cardiopulmonary bypass or when there is low cardiac output syndrome in the early postoperative phase. Postcardiotomy cardiogenic shock occurs in up to 6% of cardiac operations (4-6), with only 25% of those patients surviving to hospital discharge (4). Therefore, postcardiotomy cardiogenic shock is one of the most difficult and resource-consuming conditions, as it is associated with particularly high mortality rates. Since the risk profiles of patients scheduled for cardiac surgery procedures are continuously worsening, one may expect an increase in the number of patients requiring ECLS peri-operatively. Although these patients have only 25% of survival to hospital discharge (4), one should be aware that they would have nearly 100% mortality if they were not placed on ECLS. Although early ECLS results for postcardiotomy cardiogenic shock were found to be poor (5,7), they have been improved by continuous technological advances (5,8-10). Primary ECLS procedures may also play a significant role in cardiac surgery patients. In general, ECLS restores body perfusion and allows different treatment modalities. This may help optimize a patient’s clinical condition while waiting for a heart transplant. If a patient is not considered a suitable candidate for a heart transplant, ECLS may provide a bridge to long-term mechanical circulatory support. However, if ECLS is intended to bridge a patient to recovery (for instance in patients with acute myocarditis), then ECLS support may be considered as a treatment per se.ECLS may be used as either; 1) bridge to recovery, 2) bridge to transplant, 3) bridge to decision, or 4) bridge to intermediate or long term support. “Bridging concept” is important because a lack of exit strategy (eg, reason for bridging) may actually suggest a possible contraindication for ECLS.ECLS may play a significant role in patients with acute cardiogenic shock prior to scheduled cardiac surgery procedures such as intermediate to long term mechanical circulatory support, heart transplant, or other cardiosurgical procedures depending on the preexisting condition.Preoperative patient optimization using ECLS improves the outcomes of the level 1 Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) patients receiving a permanent ventricular assist device (11). This “bridge-to-bridge” concept consisted of preoperative stabilization of level 1 INTERMACS patients using ECLS a few days prior to ventricular assist device implantation. ECLS significantly improved renal, hepatic, and pulmonary functions (11).In addition to this, preoperative ECLS support may significantly improve outcomes in patients presenting with acute myocardial infarction (AMI) complicated with ventricular septal defect (VSD) and cardiogenic shock (12). Preoperative ECLS provided hemodynamic support, ensured end-organ perfusion, helped the myocardium to recover and allow scar tissue to be formed by reducing sheer forces, thus leading to more favorable outcomes (12).For both primary and postcardiotomy indications, our team generally prefers combined support to the heart and lungs (ECLS) rather than isolated mechanical circulatory support to the failing heart. ECLS can be implanted bedside, providing support to both the heart and the lungs simultaneously. Nowadays ECLS is available in many centers that do not perform ventricular assist device implantation. In such centers, patients should be preoperatively stabilized and transferred on support to tertiary care centers for further treatment. To facilitate this process, it would be necessary to establish an ECLS network with ECLS centers cooperating with tertiary centers that perform long term mechanical circulatory support, heart transplant, as well as complex surgical corrections. In this article, we describe our experience in the clinical application of extracorporeal life support (ECLS) and aim to analyze whether ECLS leads to acceptable clinical outcomes in patients with cardiac failure.     

Interferon-γ Causes Cardiac Myocyte Atrophy via Selective Degradation of Myosin Heavy Chain in a Model of Chronic Myocarditis

Interferon-γ (IFN-γ), a proinflammatory cytokine, has been implicated in the pathogenesis of a number of forms of heart disease including myocarditis and congestive heart failure. In fact, overexpression of IFN-γ in mice causes dilated cardiomyopathy. However, the direct effects of IFN-γ on cardiac myocytes and the mechanism by which it causes cardiac dysfunction have not been described. Here, we present the molecular pathology of IFN-γ exposure and its effect on myofibrillar proteins in isolated neonatal rat ventricular myocytes. Treatment with IFN-γ caused cardiac myocyte atrophy attributable to a specific decrease in myosin heavy chain protein. This selective degradation of myosin heavy chain was not accompanied by a decrease in total protein synthesis or by an increase in total protein degradation. IFN-γ increased both proteasome and immunoproteasome activity in cardiac myocytes and their inhibition blocked myosin heavy chain loss and myocyte atrophy, whereas inhibition of the lysosome or autophagosome did not. Collectively, these results provide a mechanism by which IFN-γ causes cardiac pathology in the setting of chronic inflammatory diseases.Both infectious and noninfectious agents including viruses, parasites, and some chemotherapeutic drugs can elicit a significant immune response in the heart. The resulting inflammation, which can persist long after resolution of the cardiac insult, causes myocarditis and is implicated in approximately 20% of sudden deaths in children and young adults.¹ The most common cause of myocarditis worldwide is the parasitic protozoan Trypanosoma cruzi, which causes Chagas disease and is the leading cause of congestive heart failure in South America.² Approximately 80% of patients with Chagas disease develop cardiac complications and 20% require heart transplantation.³ Coxsackievirus type B3, HIV, and adenovirus are the predominant causes of myocarditis in developed countries.⁴ Through direct infection of cardiac tissue and a subsequent persistent inflammatory response in the heart, a subset of these patients will develop chronic myocarditis, which is characterized by fibrosis and myocyte atrophy, and, ultimately, can lead to dilated cardiomyopathy (DCM).^5,6 Approximately 50% of patients with DCM die within 2 years of diagnosis.⁷ In one study of asymptomatic HIV-positive patients, for example, 80% had DCM, with most (83%) showing concomitant myocarditis.^4,8–10 Myocarditis therefore is associated with many different diseases, yet often is overlooked clinically, likely owing to its asymptomatic course in most patients and its association with cardiomyopathies.In cardiac infection, natural killer cells and macrophages infiltrate the myocardium and promote recruitment of T lymphocytes, which induces a robust local increase in proinflammatory cytokine production. Interferon-γ (IFN-γ), the predominant inflammatory cytokine in myocarditis, is up-regulated significantly in the myocardium of patients with Chagas disease² and is implicated in the pathogenesis of myocarditis.¹¹ During infection, IFN-γ up-regulates expression of major histocompatibility complexes I and II on infected and uninfected cells, thus enhancing the diversity of peptides displayed on these cells.¹² Inflammation that is associated with up-regulation of IFN-γ and other cytokines often persists in patients for months or years after the clearance of infection. Although initially protective, chronic inflammation is correlated with the development of DCM and heart failure in some patients.¹³ However, the mechanism by which inflammation causes DCM and heart failure is not well understood.A causative cytotoxic role for IFN-γ is supported by studies in mice: constitutive overexpression of IFN-γ in the liver, which increases serum IFN-γ levels, causes cardiac myofiber atrophy and DCM, similar to that which develops in some patients with myocarditis.^14,15 Interestingly, systemic overexpression of IFN-γ only affected the heart and did not affect skeletal or smooth muscle. However, the direct effects of IFN-γ on cardiac myocytes were not determined. Here, we examine the effects of IFN-γ on cardiac myocytes in isolation from the complicated systemic and local effects of infection and suggest a mechanism for the specificity of cytotoxicity in the heart.     

Noninvasive measurement of cardiac performance in recovery from exercise in heart failure patients

OBJECTIVE:

To examine the association between cardiac performance during recovery and the severity of heart failure, as determined by clinical and cardiopulmonary exercise test responses.

METHODS:

As part of a retrospective cohort study, 46 heart failure patients and 13 normal subjects underwent cardiopulmonary exercise testing while cardiac output was measured using a noninvasive device. Cardiac output in recovery was expressed as the slope of a single exponential relationship between cardiac output and time; the recovery-time constant was assessed in relation to indices of cardiac function, along with clinical, functional, and cardiopulmonary exercise responses.

RESULTS:

The recovery time constant was delayed in patients with heart failure compared with normal subjects (296.7±238 vs. 110.1±27 seconds, p <0.01), and the slope of the decline of cardiac output in recovery was steeper in normal subjects compared with heart failure patients (p<0.001). The slope of the decline in cardiac output recovery was inversely related to peak VO₂ (r = -0.72, p<0.001) and directly related to the VE/VCO₂ slope (r = 0.57, p<0.001). Heart failure patients with abnormal recovery time constants had lower peak VO₂, lower VO₂ at the ventilatory threshold, lower peak cardiac output, and a heightened VE/VCO₂ slope during exercise.

CONCLUSIONS:

Impaired cardiac output recovery kinetics can identify heart failure patients with more severe disease, lower exercise capacity, and inefficient ventilation. Estimating cardiac output in recovery from exercise may provide added insight into the cardiovascular status of patients with heart failure.     

Glucocorticoids Induce Cardiac Fibrosis via Mineralocorticoid Receptor in Oxidative Stress: Contribution of Elongation Factor Eleven-Nineteen Lysine-Rich Leukemia (ELL)

Background

Cardiac fibrosis is considered to be a crucial factor in the development of heart failure. Blockade of the mineralocorticoid receptor (MR) attenuated cardiac fibrosis and improved the prognosis of patients with chronic heart failure but the ligand for MR and the regulatory mechanism of MR pathway in the diseased heart are unclear. Here, we investigated whether glucocorticoids can promote cardiac fibrosis through MR in oxidative stress and the involvement of elongation factor eleven-nineteen lysine-rich leukemia (ELL), a co-activator of MR, in this pathway.

Methods and Results

The MR antagonist eplerenone attenuated corticosterone-induced collagen synthesis assessed by [³H]proline incorporation in rat neonatal cultured cardiac fibroblasts in the presence of H₂O₂, as an oxidative stress but not in the absence of H₂O₂. H₂O₂ increased the ELL expression levels and MR-bound ELL. ELL expression levels and MR-bound ELL were also increased in the left ventricle of heart failure model rats with significant fibrosis and enhanced oxidative stress. Eplerenone did not attenuate corticosterone-induced increase of [³H]proline incorporation in the presence of H₂O₂ after knockdown of ELL expression using small interfering RNA in cardiac fibroblasts.

Conclusion

Glucocorticoids can promote cardiac fibrosis via MR in oxidative stress, and oxidative stress modulates MR response to glucocorticoids through the interaction with ELL. Preventing cardiac fibrosis by modulating glucocorticoid-MR-ELL pathway may become a new therapeutic strategy for heart failure.     

Macrophages and cardiac fibroblasts are the main producers of eotaxins and regulate eosinophil trafficking to the heart

Cardiac manifestations are a major cause of morbidity and mortality in patients with eosinophil‐associated diseases. Eosinophils are thought to play a pathogenic role in myocarditis. We investigated the pathways that recruit eosinophils to the heart using a model of eosinophilic myocarditis, in which experimental autoimmune myocarditis (EAM) is induced in IFNγ^?/?IL‐17A^?/? mice. Two conditions are necessary for efficient eosinophil trafficking to the heart: high eotaxin (CCL11, CCL24) expression in the heart and expression of the eotaxin receptor CCR3 by eosinophils. We identified cardiac fibroblasts as the source of CCL11 in the heart interstitium. CCL24 is produced by F4/80⁺ macrophages localized at inflammatory foci in the heart. Expression of CCL11 and CCL24 is controlled by Th2 cytokines, IL‐4 and IL‐13. To determine the relevance of this pathway in humans, we analyzed endomyocardial biopsy samples from myocarditis patients. Expression of CCL11 and CCL26 was significantly increased in eosinophilic myocarditis compared to chronic lymphocytic myocarditis and positively correlated with the number of eosinophils. Thus, eosinophil trafficking to the heart is dependent on the eotaxin‐CCR3 pathway in a mouse model of EAM and associated with cardiac eotaxin expression in patients with eosinophilic myocarditis. Blocking this pathway may prevent eosinophil‐mediated cardiac damage.     

FGL2 knockdown improves heart function through regulation of TLR9 signaling in the experimental autoimmune myocarditis rats

Fibrinogen-like protein 2 (FGL2) is an important immune regulator of both innate and adaptive response. It is present on the surface of macrophages and endothelial cells, and can be constitutively secreted by CD4⁺CD8⁺ T cells. Previous studies showed that FGL2 is a potential target for the treatment of experimental autoimmune myocarditis. However, the molecular mechanism of the roles of FGL2 in experimental autoimmune myocarditis is poorly understood. Here, we silenced FGL2 gene by using FGL2-RNAi lentivirus to reveal the heart function in experimental autoimmune myocarditis rats. We found that the cardiac myosin of pigs’ hearts induced Lewis rats to come into being as autoimmune myocarditis. TLR9 was upregulated in the heart of experimental autoimmune myocarditis rats. After primary immunization (21 day), the cardiac function of the myocarditis model group improved (P < 0.05). Significantly, the levels of INF-α and NF-κB in the FGL2-RNAi-treated group were lower compared to those in the myocarditis model (EAM) group (P < 0.05). Notably, the inflammation score correspondence with the protein and mRNA levels of TLR9 in myocardial tissues was markedly reduced compared to that in the EAM group (P < 0.05). These results support a role of FGL2 to alleviate inflammatory situation in the myocardium through regulation of the TLR9 signaling pathway in the experimental autoimmune myocarditis rats.     

Bedside echocardiography is useful in assessing children with fluid and inotrope resistant septic shock

Objective:

To report changes in the cardiovascular management of fluid and inotropic resistant septic shock in children based on echocardiography.

Design:

Retrospective case series.

Setting:

Tertiary care Pediatric Intensive Care Unit (PICU), Chennai.

Patients:

Twenty-two patients with unresolved septic shock after 60 ml/kg fluid plus inotropic agents in the first hour.

Interventions:

Bedside echocardiography (echo) within 6 h of admission to the PICU.

Results:

Over a 28-month period, of 37 patients with septic shock, 22 children remained in shock despite 60 ml/kg fluid and dopamine and/or dobutamine infusions as per guidelines. On clinical exam, 12 patients had warm shock and ten had cold shock, however, six exhibited an unusual pattern of cold shock with wide pulse pressures on invasive arterial monitoring. The most common echocardiographic finding was uncorrected hypovolemia in 12/22 patient while ten patients had impaired left ± right ventricular function. Echocardiography permitted an appreciation of the underlying disordered pathophysiology and a rationale for adjustment of treatment. Shock resolved in 17 (77%) and 16 patients (73%) survived to discharge.

Conclusions:

Bedside echo provided crucial information that was not apparent on clinical assessment and affords a simple noninvasive tool to determine the cause of low cardiac output in patients who remain in shock despite 60 ml/kg fluid and inotropic support. Most patients in our series had vasodilatory shock with wide pulse pressures and most common finding on echo was uncorrected hypovolemia. The echo findings allowed adjustment of therapy which was not possible based on clinical examination alone.     

Pathogens and outcomes in pediatric septic shock patients supported by extracorporeal membrane oxygenation

Background

Refractory septic shock is the leading cause of mortality in children. There is limited evidence to support extracorporeal membrane oxygenation (ECMO) use in pediatric septic shock. We described the etiology and outcomes of septic patients in our institution and attempted to find predictive factors.

Acute myocarditis presenting as cardiac tamponade

We report a case of acute fulminant myocarditis presenting with cardiac tamponade and shock. The patient was managed in the coronary care unit with emergency pericardiotomy, invasive hemodynamic monitoring, and supportive therapy for cardiac failure. Pleural effusion and pneumonia complicated her clinical course. She responded well to therapy with normalization of left ventricular systolic function. This case demonstrates the potential for complete recovery with appropriate management in acute myocarditis even with a fulminant course.     

Vasoactive Inotrope Score as a tool for clinical care in children post cardiac surgery

Background:

Neonates and infants undergoing heart surgery on cardiopulmonary bypass (CPB) are at high risk for significant post-operative morbidity and mortality. Hence, there is a need to identify and quantify clinical factors during the early post-operative period that are indicative of short-term as well as long-term outcomes. Multiple inotrope scores have been used in practice to quantify the amount of cardiovascular support received by neonates.

Aims:

The goal of this study was to determine the association between inotropic/vasoactive support and clinical outcomes in children after open cardiac surgery.

Materials and Methods:

This is a retrospective analysis of the 208 patients who underwent cardiac surgery for congenital heart disease at a tertiary pediatric cardiac surgery Intensive Care Unit (ICU) from January 2012 to March 2013. Multiple demographic, intra-operative and post-operative variables were recorded, including the Vasoactive Inotrope Score (VIS).

Results:

A total of 208 patients underwent cardiac surgery for congenital heart disease in the study period. The mean age and weight in the study were 66.94 months and 16.31 kg, respectively. Statistically significant associations were found in the various variables and VIS, including infancy, weight < 10 kg, CPB time, pump failure and post-operative variables like sepsis, hematological complications, hepatic dysfunction, acute kidney injury during admission, mortality, prolonged ventilator requirement, CPB time (in min) and hospital stay.

Conclusions:

Inotrope score and its adaptations are an excellent tool to measure illness severity, deciding interventions and during parental counseling in the pediatric cardiac surgery ICUs.     

Fluid volume kinetics of dilutional hyponatremia; a shock syndrome revisited

OBJECTIVE:

To evaluate whether the pathophysiology of shock syndromes can be better understood by comparing central hemodynamics with kinetic data on fluid and electrolyte shifts.

METHODS:

We studied the dilutional hyponatremic shock that developed in response to overhydration with electrolyte-free irrigating fluid – the so-called ‘transurethral resection syndrome'' – by comparing cardiac output, arterial pressures, and volume kinetic parameters in 17 pigs that were administered 150 ml/kg of either 1.5% glycine or 5% mannitol by intravenous infusion over 90 minutes.

RESULTS:

Natriuresis appeared to be the key factor promoting hypovolemic hypotension 15–20 minutes after fluid administration ended. Excessive sodium excretion, due to osmotic diuresis caused by the irrigant solutes, was associated with high estimates of the elimination rate constant (k₁₀) and low or negative estimates of the rate constant describing re-distribution of fluid to the plasma after translocation to the interstitium (k₂₁). These characteristics indicated a high urinary flow rate and the development of peripheral edema at the expense of plasma volume and were correlated with reductions in cardiac output. The same general effects of natriuresis were observed for both irrigating solutions, although the volume of infused 1.5% glycine had a higher tendency to enter the intracellular fluid space.

CONCLUSION:

Comparisons between hemodynamics and fluid turnover showed a likely sequence of events that led to hypovolemia despite intravenous administration of large amounts of fluid.     

Dysregulation of Heart Rhythm During Sleep in Leptin-Deficient Obese Mice

Study Objectives:

Sleep deeply affects cardiac autonomic control, the impairment of which is associated with cardiovascular mortality. Obesity entails increased cardiovascular risk and derangements in sleep and cardiac autonomic control. We investigated whether cardiac autonomic control is impaired during sleep in ob/ob mice with morbid obesity caused by congenital leptin deficiency.

Design:

Indexes of cardiac autonomic control based on spontaneous cardiovascular fluctuations were compared between ob/ob and lean wild-type (+/+) mice during wakefulness, non-rapid eye movement sleep (NREMS), and rapid eye movement sleep (REMS).

Setting:

N/A

Patients or Participants:

7 ob/ob and 11 +/+ male mice.

Interventions:

Instrumentation with electrodes for sleep recordings and a telemetric transducer for measuring blood pressure and heart period.

Measurements and Results:

In ob/ob mice, the variability of heart period and cardiac baroreflex sensitivity (sequence technique) were significantly lower than in +/+ mice during each wake-sleep state. The vagal modulation of heart period was significantly weaker in ob/ob than in +/+ mice during NREMS and REMS. In ob/ob mice, the cross-correlation function between heart period and blood pressure suggested that the baroreflex contribution to cardiac control was lower than in +/+ mice during wakefulness and NREMS, whereas the contribution of central autonomic commands was lower than in +/+ mice during NREMS and REMS.

Conclusions:

These data indicate a dysregulation of cardiac autonomic control during sleep in ob/ob mice. Ob/ob mice may represent a useful tool to understand the molecular pathways that lead to cardiac autonomic dysregulation during sleep in obesity.

Citation:

Silvani A; Bastianini S; Berteotti C; Franzini C; Lenzi P; Lo Martire V; Zoccoli G. Dysregulation of heart rhythm during sleep in leptin-deficient obese mice. SLEEP 2010;33(3):355-361.     

Adenosine A2B Receptors on Cardiac Stem Cell Antigen (Sca)-1–Positive Stromal Cells Play a Protective Role in Myocardial Infarction

Transplantation of mesenchymal stem-like cells to the heart is known to improve cardiac recovery in animal models of myocardial infarction (MI). Because stimulation of A_2B adenosine receptors on mouse cardiac stem cell antigen (Sca)-1⁺CD31⁻ mesenchymal stem-like cells significantly up-regulates their secretion of pro-angiogenic factors, we hypothesized that ablation of the A_2B receptor signaling in these cells would reduce their ability to improve vascularization of the infarct area seen after transplantation. Wild-type (WT) C57BL/6 mice underwent permanent left coronary artery ligation and received intramyocardial injections of Sca-1⁺CD31⁻ cells generated from WT or A_2B receptor knockout (A_2BKO) mice or the same volume of cell-free saline. Only 12% to 16% of injected cells remained in the ventricles 1 week later; there was no significant difference between WT and A_2BKO cell survival. Transplantation of WT, but not A_2BKO, cells significantly reduced both post-MI decline in cardiac function and adverse remodeling compared with that seen in control hearts. Morphological analysis conducted 4 weeks after MI revealed significantly increased vascularization of the infarct areas and reduced myocardial scarring in animals treated with WT, but not with A_2BKO, cells compared with control. Thus, our study demonstrated that the A_2B receptor signaling linked to up-regulation of pro-angiogenic factors in cardiac Sca-1⁺CD31⁻ stromal cells is essential for overall improvement of cardiac recovery seen after their transplantation to the injured heart.Mesenchymal stem-like cells of various tissue origins have been proposed to be used in cell-based transplantation therapy to enhance tissue repair and functional recovery after myocardial infarction (MI). Among them, cardiac mesenchymal stem-like cells have been consistently shown to possess superior paracrine potency and myocardial protection efficacy compared with stem/progenitor cells originated from other tissues.^1,2 In the mouse heart, these cells are represented by a population of stromal cells characterized by the expression of stem cell antigen (Sca)-1 on their surface and the absence of the endothelial cell surface marker, CD31.^3–9 Several groups independently reported that the delivery of cardiac Sca-1⁺CD31⁻ cell populations to the heart resulted in improved revascularization of injured tissue and attenuated decline of cardiac function in animal models of MI.^6,9–11 Although the precise mechanism of these protective effects remains unknown, the early assumption that these cells can replace damaged cardiomyocytes has recently given way to the realization that they also, and perhaps mainly, exert a beneficial effect via the release of paracrine factors.^3,12–17 As such, the beneficial properties of transplanted cells are likely regulated by local factors present in the ischemic tissue, including high levels of extracellular adenosine.Adenosine is an endogenously produced signaling molecule that binds to the family of extracellular G-protein–coupled seven transmembrane receptors, which include A₁, A_2A, A_2B, and A₃ subtypes. Adenosine concentrations in the myocardial interstitium remain low in normal conditions. Myocardial ischemia is known to considerably increase extracellular adenosine levels.^18,19 MI results in even larger levels of extracellular adenosine because of its massive release from damaged cells and catabolism of coreleased adenine nucleotides. Subsequent inflammation in the injured myocardium may further increase extracellular adenosine levels as the result of cell stress and tissue hypoxia.²⁰ Therefore, extracellular adenosine becomes an important part of the tissue microenvironment generated by myocardial ischemia and infarction.Recently, we found that stimulation of A_2B adenosine receptors on mouse cardiac Sca-1⁺CD31⁻ stromal cells significantly increased secretion of pro-angiogenic factors.²¹ In this study, we tested the hypothesis that the A_2B receptor signaling in these cells is important for their therapeutic effects seen after transplantation to the heart after MI.     

Comparison of the effects of propofol and midazolam on inflammation and oxidase stress in children with congenital heart disease undergoing cardiac surgery

Purpose

To investigate and compare the effects of propofol and midazolam on inflammation and oxidase stress in children with congenital heart disease undergoing cardiac surgery.

Materials and Methods

Thirty-two ASA class I-II children with congenital heart disease undergoing cardiac surgery were randomly divided into two groups: propofol combined with low dose fentanyl (PF group, n = 16) and midazolam combined with low dose fentanyl (MF group, n = 16). Tracheal extubation time and length of Intensive Care Unit (ICU) stay were recorded. Blood samples were taken before operation (T₀), at 2 h after release of the aorta cross-clamp (T₃) and at 24 h after operation (T₄) to measure interleukin 6 (IL-6), IL-8, superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Myocardium samples were collected at 10-20 min after aorta cross-clamp (T₁) and at 10-20 min after the release of the aorta cross-clamp (T₂) to detect heme oxygenase-1 (HO-1) expression.

Results

Tracheal extubation time and length of ICU stay in PF group were significantly shorter than those of the MF group (p < 0.05, respectively). After cardiopulmonary bypass, IL-6, IL-8 and MDA levels were significantly increased, and the SOD level was significantly reduced in both two groups, but PF group exhibited lower IL-6, IL-8 and MDA levels and higher SOD levels than the MF group (p < 0.05, respectively). The HO-1 expression in the PF group was significantly higher than that in MF group at the corresponding time points (p < 0.05, respectively).

Conclusion

Propofol is superior to midazolam in reducing inflammation and oxidase stress and in improving post-operation recovery in children with congenital heart disease undergoing cardiac surgery.     

Prognostic value of venoarterial carbon dioxide gradient in patients with severe sepsis and septic shock

Aim

To investigate the changes in the venoarterial carbon-dioxide gradient (V-a Pco₂) and its prognostic value for survival of patients with severe sepsis and septic shock.

Methods

The study was conducted in General Hospital Holy Spirit from January 2004 to December 2007 and included 71 conveniently sampled adult patients (25 women and 46 men), who fulfilled the severe sepsis and septic shock criteria and were followed for a median of 8 days (interquartile range, 12 days). The patients were divided in two groups depending on whether or not they had been mechanically ventilated. Both groups of patients underwent interventions with an aim to achieve hemodynamic stability. Mechanical ventilation was applied in respiratory failure. Venoarterial carbon dioxide gradient was calculated from the difference between the partial pressure of arterial CO₂ and the partial pressure of mixed venous CO₂, which was measured with a pulmonary arterial Swan-Ganz catheter. The data were analyzed using Kaplan-Meier survival analysis, along with a calculation of the hazard ratios.

Results

There was a significant difference between non-ventilated and ventilated patients, with almost 4-fold greater hazard ratio for lethal outcome in ventilated patients (3.85; 95% confidence interval, 1.64-9.03). Furthermore, the pattern of changes of many other variables was also different in these two groups (carbon dioxide-related variables, variables related to acid-base status, mean arterial pressure, systemic vascular resistance, lactate, body mass index, Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology II Score, and Sepsis-related Organ Failure Assessment score). Pco₂ values (with a cut-off of 0.8 kPa) were a significant predictor of lethal outcome in non-ventilated patients (P = 0.015) but not in ventilated ones (P = 0.270).

Conclusion

V-a Pco₂ was a significant predictor of fatal outcome only in the non-ventilated group of patients. Ventilated patients are more likely to be admitted with a less favorable clinical status, and other variables seem to have a more important role in their outcome.Although oxygen delivery (Do₂) in septic shock can be elevated, oxygen consumption (Vo₂) is impaired (1). This could be a consequence of mitochondrial dysfunction in sepsis (2,3). Blood circulation is slow and consequently the elimination of CO₂ from the tissue is slower, making the tissue CO₂ concentration high. Venoarterial carbon dioxide gradient (V-a Pco₂) was calculated from the difference between the partial pressure of arterial CO₂ (Paco₂) and the partial pressure of mixed venous CO₂ (Pvco₂), which was measured with a pulmonary arterial Swan-Ganz catheter. The venoarterial CO₂ gradient (V-a Pco₂) is influenced by two other factors: the dissociative curve of CO₂ and tissue blood flow. The curve of CO₂ dissociation from hemoglobin follows the so-called Haldane''s effect, in which oxygen and its bonding with hemoglobin allows easier release of carbon dioxide in lungs (4). Experimental models have shown that in toximia, venous hypercapnia is a more significant contributor to the increase in the venoarterial CO₂ gradient than arterial CO₂ values (4-7). Elevated V-a Pco₂ has also been described in patients with sepsis, cardiogenic shock, acute myocardial infarction, and congestive heart failure, as well as cardiac arrest following cardiopulmonary resuscitation and heart surgery (8-13).In septic patients, the significance of the connection between an elevation of V-a Pco₂ and the course and outcome of the illness is not sufficiently known. It has been established that V-a Pco₂ shows a negative exponential relationship with the cardiac index (CI) (14,15). The negative association with CI has been observed not only in septic shock patients but also in postoperative patients without sepsis. In patients with a lethal outcome, CI was reduced, but V-a Pco₂ was not an independent predictor of outcome (14,16).The aim of this study was to investigate the changes in V-a Pco₂ to better understand the possibilities of using it as a predictor of clinical outcomes in patients with severe sepsis and septic shock.     

Norepinephrine Remains Increased in the Six-Minute Walking Test after Heart Transplantation

OBJECTIVE:

We sought to evaluate the neurohormonal activity in heart transplant recipients and compare it with that in heart failure patients and healthy subjects during rest and just after a 6-minute walking test.

INTRODUCTION:

Despite the improvements in quality of life and survival provided by heart transplantation, the neurohormonal profile is poorly described.

METHODS:

Twenty heart transplantation (18 men, 49±11 years and 8.5±3.3 years after transplantation), 11 heart failure (8 men, 43±10 years), and 7 healthy subjects (5 men 39±8 years) were included in this study. Blood samples were collected immediately before and during the last minute of the exercise.

RESULTS:

During rest, patients’ norepinephrine plasma level (659±225 pg/mL) was higher in heart transplant recipients (463±167 pg/mL) and heathy subjects (512±132), p<0.05. Heart transplant recipient’s norepinephrine plasma level was not different than that of healthy subjects. Just after the 6-minute walking test, the heart transplant recipient’s norepinephrine plasma level (1248±692 pg/mL) was not different from that of heart failure patients (1174±653 pg/mL). Both these groups had a higher level than healthy subjects had (545±95 pg/mL), p<0.05.

CONCLUSION:

Neurohormonal activity remains increased after the 6-minute walking test after heart transplantation.     

Successful treatment of near-fatal fulminant myocarditis using bi-ventricular assist device support

Fulminant myocarditis is a rare but fatal serious disease that may cause prolonged native cardiac dysfunction with multiorgan failure despite temporary mechanical circulatory support with percutaneous venoatrial extracorporeal membrane oxygenation (VA-ECMO) or intraaortic balloon pumping (IABP). A 26-year-old man with fulminant myocarditis developed life-threatening multiorgan failure after 8 days support by VA-ECMO and IABP. He was transferred to our institution with prolonged cardiac dysfunction on hospital day 8; massive pulmonary edema developed into severe pulmonary dysfunction. Immediately after admission, VA-ECMO and IABP were switched to a paracorporeal pneumatic left ventricular assist device (LVAD) and right centrifugal ventricular assist device with an ECMO circuit shunting from the right ventricle to the pulmonary artery (RVAD-ECMO). After intensive care focusing on respiratory dysfunction, ECMO was successfully weaned, and the right ventricular assist device was switched to a durable paracorporeal pneumatic right ventricular assist device. The paracorporeal bi-ventricular assist devices were finally replaced with an implantable non-pulsatile LVAD on hospital day 181. Currently, 1 year after discharge, the patient is at home awaiting heart transplantation. Combined LVAD and RVAD-ECMO appear to be useful for resolving severe pulmonary edema due to unnecessarily long VA-ECMO support as well as kidney or liver dysfunction caused by circulatory collapse.