Heart failure gene therapy: the path to clinical practice

Gene therapy, aimed at the correction of key pathologies being out of reach for conventional drugs, bears the potential to alter the treatment of cardiovascular diseases radically and thereby of heart failure. Heart failure gene therapy refers to a therapeutic system of targeted drug delivery to the heart that uses formulations of DNA and RNA, whose products determine the therapeutic classification through their biological actions. Among resident cardiac cells, cardiomyocytes have been the therapeutic target of numerous attempts to regenerate systolic and diastolic performance, to reverse remodeling and restore electric stability and metabolism. Although the concept to intervene directly within the genetic and molecular foundation of cardiac cells is simple and elegant, the path to clinical reality has been arduous because of the challenge on delivery technologies and vectors, expression regulation, and complex mechanisms of action of therapeutic gene products. Nonetheless, since the first demonstration of in vivo gene transfer into myocardium, there have been a series of advancements that have driven the evolution of heart failure gene therapy from an experimental tool to the threshold of becoming a viable clinical option. The objective of this review is to discuss the current state of the art in the field and point out inevitable innovations on which the future evolution of heart failure gene therapy into an effective and safe clinical treatment relies.

[Psychophysiologic manifestations, psychological and somatic risk factors and the physician-patient relationship in patients with heart diseases]

In daily medicine we often see patients complaining about thoracic pain. There is little doubt about the etiology in the most cases, but several patients continue posing diagnostic problems. There are different pathophysiological views to understand the situation of those patients, and it is important to determine their mental and psychological conditions. For this purpose, the focus on transference and countertransference phenomena has to be stressed. With these elements it will be possible to determine the diagnostic and therapeutic approach to those patients to reassure them and to justify investigations.

Treatment of recurrent rejection in heart transplantation: cytolytic therapy or bolus steroids?

OBJECTIVES: The treatment of recurrent rejection in heart transplant recipients has been a controversial issue for many years. The intent of this retrospective study was to perform a risk-benefit analysis between treatment strategies with bolus steroids only versus anti-thymocyte globulins (RATG; 1.5 mg/kg q 4 days). METHODS: Between 1986 and 1993, 69 of 425 patients (17 male, 52 female; mean age 44 +/- 11 years) who had more than one rejection/patient per month (rej/pt per mo) in the first 3 postoperative months were defined as recurrent rejectors. RESULTS: Repetitive methylprednisolone bolus therapy (70 mg/kg q 3 days) was given in 27 patients (group M; 1.4 +/- 0.2 rej/pt per mo) and RATG therapy for one of the rejection episodes of the 42 remaining patients (group A; 1.5 +/- 0.2 rej/pt per mo). The quality of triple drug immunosuppression in the two study groups was comparable. The rejection-free interval (RFI) following RATG treatment in group A was 21.6 +/- 10 days and 22 +/- 11 in group M. In group M, 3 of 27 patients (11%) had a rejection treatment-related infection (2 bacterial; 1 viral) versus 6 of the 42 patients of group A (14.2%; bacterial 1, viral 5). During postoperative months 3-24, 0.15 +/- 0.12 rej/pat per mo were observed in group M and 0.21 +/- 0.13 rej/pat per mo in group A (n.s.). In this 21-month period cytolytic therapy for rejection was initiated in 8 of the remaining 21 patients of group M (38%) and 15 of the remaining 37 patients of group A (40.5%). The absolute survival and the individual causes of death were not affected by the type of initial treatment of recurrent rejection. The actuarial freedom of graft atherosclerosis is comparable in the two groups with 78% in group A versus 79% in group M free of graft atherosclerosis at 3 years postoperatively. CONCLUSIONS: A comparison of cytolytic therapy versus repeated applications of bolus steroids for treatment of recurrent rejection reveals no significant difference in the long-term patient outcome with respect to the incidence of future rejection episodes and survival.

Prevalence of heart disease in symptomatic cats: an overview from 1998 to 2005

A total of 408 cats with various cardiovascular problems has been presented to two investigational clinics during the last 8 years. The number of yearly examinations has steadily increased during this period. Definitive cardiovascular disease was diagnosed in 287 cats, whereby hypertrophic cardiomyopathy (HCM) was the most common diagnosis with 67.6%. Congenital cardiovascular malformations were found in 11.8% of the cases. Ventricular septal defect (VSD) was the most frequent anomaly, in contrast to previously published studies. The ECG was found to be relatively non-specific and insensitive for the diagnosis of heart disease: Its usefulness lies in the recognition and diagnosis of cardiac arrhythmias. The radiographically recognized changes were also non-specific for certain heart diseases. Radiographs of the thorax are especially useful in the evaluation of cardiomegaly, and secondary signs of congestion.

[The role of percutaneus coronary interventions in the treatment of coronary artery disease]

In industrial countries, cardiovascular diseases remain the primary cause of death. This review summarizes the role of percutaneous coronary interventions (PCI) in the treatment of coronary heart disease. Interventional therapy of coronary artery disease was initiated in 1977 with the introduction of balloon angioplasty by Andreas Grüntzig in Zurich. Technical progress since has been related to construction and materials of catheters, but also to digital processing of x-ray imaging. Additional methods - rotablation, atherectomy, laser, intravascular ultrasound, and most importantly stent implantation were developed. Only stents significantly changed the procedure. They are today an integral part of PCI.

Application, tolerance and safety of fondaparinux therapy in a German hospital: a prospective single-centre experience.

INTRODUCTION The pentasaccharide fondaparinux is widely approved for prophylaxis and treatment of thromboembolic diseases and therapy of acute coronary syndrome. It is also used off-label in patients with acute, suspected or antecedent heparin-induced thrombocytopenia (HIT). The aim of this prospective observational cohort study was to document fondaparinux' prescription practice, tolerance and therapy safety in a representative mixed German single-centre patient cohort. PATIENTS AND METHODS Between 09/2008 - 04/2009, 231 consecutive patients treated with fondaparinux were enrolled. Medical data were obtained from patient's records. The patients were clinically screened for thrombosis (Wells score), sequelae of HIT (4T's score), and bleeding complications (ISTH-criteria) and subjected to further assessment (i.e. sonography, HIT-diagnostics), if necessary. The mortality rate was assessed 30 days after therapy start. RESULTS Overall, 153/231 patients had a prophylactic, 74/231 patients a therapeutic, and 4/231 patients a successive prophylactic/therapeutic indication. In 11/231 patients fondaparinux was used due to suspected/antecedent HIT, in 5/231 patients due to a previous cutaneous delayed-type hypersensitivity to heparins. Other indications were rare. Three new/progressive thromboses were detected. No cases of HIT, major bleedings, or fatalities occurred. CONCLUSIONS Fondaparinux was well tolerated and was safe in prophylaxis and therapy; prescriptions mostly followed the current approval guidelines and were rarely related to HIT-associated indications (<5% of prescriptions), which is in contrast to previous study results in the U.S. (>94% of prescriptions were HIT-associated). A trend towards an individualised fondaparinux use based on the compound's inherent properties and the patients' risk profiles, i.e., antecedent HIT, bone fractures, heparin allergy, was observed.

Assessment of right ventricular systolic function: Comparison between cardiac magnetic resonance derived ejection fraction and pulsed-wave tissue Doppler imaging of the tricuspid annulus

Systolic right ventricular (RV) function is an important predictor in the course of various congenital and acquired heart diseases. Its practical determination by echocardiography remains challenging. We compared routine assessment of lateral tricuspid annular systolic motion velocity (TV(lat), cm/s) using pulsed-wave tissue Doppler imaging from the apical 4-chamber view with cardiac magnetic resonance (CMR) as reference method.

A locus on chromosome 5 is associated with dilated cardiomyopathy in Doberman Pinschers

Dilated cardiomyopathy (DCM) is a heterogeneous group of heart diseases with a strong genetic background. Currently, many human DCM cases exist where no causative mutation can be identified. DCM also occurs with high prevalence in several large dog breeds. In the Doberman Pinscher a specific DCM form characterized by arrhythmias and/or echocardiographic changes has been intensively studied by veterinary cardiologists. We performed a genome-wide association study in Doberman Pinschers. Using 71 cases and 70 controls collected in Germany we identified a genome-wide significant association to DCM on chromosome 5. We validated the association in an independent cohort collected in the United Kingdom. There is no known DCM candidate gene under the association signal. Therefore, DCM in Doberman Pinschers offers the chance of identifying a novel DCM gene that might also be relevant for human health.

Neuregulin-1 beta attenuates doxorubicin-induced alterations of excitation-contraction coupling and reduces oxidative stress in adult rat cardiomyocytes

Treatment of metastatic breast cancer with doxorubicin (Doxo) in combination with trastuzumab, an antibody targeting the ErbB2 receptor, results in an increased incidence of heart failure. Doxo therapy induces reactive oxygen species (ROS) and alterations of calcium homeostasis. Therefore, we hypothesized that neuregulin-1 beta (NRG), a ligand of the cardiac ErbB receptors, reduces Doxo-induced alterations of EC coupling by triggering antioxidant mechanisms. Adult rat ventricular cardiomyocytes (ARVM) were isolated and treated for 18-48 h. SERCA protein was analyzed by Western blot, EC coupling parameters by fura-2 and video edge detection, gene expression by RT-PCR, and ROS by DCF-fluorescence microscopy. At clinically relevant doses Doxo reduced cardiomyocytes contractility, SERCA protein and SR calcium content. NRG, similarly as the antioxidant N-acetylcystein (NAC), did not affect EC coupling alone, but protected against Doxo-induced damage. NRG and Doxo showed an opposite modulation of glutathione reductase gene expression. NRG, similarly as NAC, reduced peroxide- or Doxo-induced oxidative stress. Specific inhibitors showed, that the antioxidant action of NRG depended on signaling via the ErbB2 receptor and on the Akt- and not on the MAPK-pathway. Therefore, NRG attenuates Doxo-induced alterations of EC coupling and reduces oxidative stress in ARVM. Inhibition of the ErbB2/NRG signaling pathway by trastuzumab in patients concomitantly treated with Doxo might prevent beneficial effects of NRG in the myocardium.

Combined cardiac and lung volume reduction surgery

Coronary artery disease is prevalent in patients who have severe emphysema and who are being considered for lung volume reduction surgery (LVRS). Significant valvular heart diseases may also coexist in these patients. Few thoracic surgeons have performed LVRS in patients who have severe cardiac diseases. Conversely, few cardiac surgeons have been willing to undertake major cardiac surgery in patients who have severe emphysema. This report reviews the evidence regarding combined cardiac surgery and LVRS to determine the optimal management strategy for patients who have severe emphysema and who are suitable for LVRS, but who also have coexisting significant cardiac diseases that are operable.

Electroanatomic mapping of the endocardium. Implication for catheter ablation of ventricular tachycardia.

The electroanatomic mapping system Carto((R)) with its combination of anatomic and electrophysiologic information has substantially improved our understanding of arrhythmia mechanisms and substrates in patients with ventricular tachycardia (VT) and structural heart disease. Identification of the individual arrhythmogenic substrate and successful ablation guided by the combination of sinus rhythm voltage mapping and conventional electrophysiologic techniques like pace and activation/entrainment mapping are best described for patients with recurrent VT in remote myocardial infarction. In about 75-90% of the patients, the target VT can be ablated with acute success and the patients remain free of any VT recurrence in up to 75%. First results of electroanatomically guided ablation in patients with arrhythmogenic right ventricular dysplasia are promising. Data on ablation of VT in other structural heart diseases are very limited, since the arrhythmogenic substrate is very diffuse, e. g., in dilated cardiomyopathy, or there are only small patient numbers, e. g., for cardiac sarcoidosis or monomorphic VT after repair of congenital heart disease. In this article, the current status of electroanatomically guided endocardial mapping and ablation of VT in patients with structural heart disease is described.

Rescue of neonatal cardiac dysfunction in mice by administration of cardiac progenitor cells in utero

Striated preferentially expressed gene (Speg) is a member of the myosin light chain kinase family. We previously showed that disruption of the Speg gene locus in mice leads to a dilated cardiomyopathy with immature-appearing cardiomyocytes. Here we show that cardiomyopathy of Speg(-/-) mice arises as a consequence of defects in cardiac progenitor cell (CPC) function, and that neonatal cardiac dysfunction can be rescued by in utero injections of wild-type CPCs into Speg(-/-) foetal hearts. CPCs harvested from Speg(-/-) mice display defects in clone formation, growth and differentiation into cardiomyocytes in vitro, which are associated with cardiac dysfunction in vivo. In utero administration of wild-type CPCs into the hearts of Speg(-/-) mice results in CPC engraftment, differentiation and myocardial maturation, which rescues Speg(-/-) mice from neonatal heart failure and increases the number of live births by fivefold. We propose that in utero administration of CPCs may have future implications for treatment of neonatal heart diseases.

Acute Angioedema Triggered by Daptomycin.

INTRODUCTION Daptomycin is a cyclic lipopeptide antibiotic, frequently administered for Staphylococcus aureus bloodstream infections. Numerous studies have shown that daptomycin is relatively safe and well tolerated. Serious adverse events possibly related to this antimicrobial compound are rare. We report a case of acute angioedema triggered by daptomycin. CASE REPORT A 60-year-old woman with S. aureus bacteremia without identified source was treated intravenously with high-dose beta-lactams at our institution. Because S. aureus bacteremia persisted on day 6, and in parallel, acute kidney injury developed, antimicrobial treatment was switched to a combination therapy with daptomycin and ceftriaxone. Shortly after completion of the first daptomycin administration, the patient developed lip and tongue swelling and dyspnea. Acute angioedema was clinically evident. Antibiotic therapy was switched to vancomycin, and the further clinical course was favorable. An intradermal test showed a significant wheal diameter for daptomycin, but negative results for ceftriaxone. CONCLUSION The association with daptomycin in this case is either probable or certain. Clinicians should be aware that daptomycin can cause immediate-type hypersensitivity reactions, including acute angioedema, even upon first administration.

[Diagnosis and therapy of depression in the heart disease patient]

Even though depressions and depressive symptoms are frequently observed in patients with medical diseases, their psychological problems are often neither diagnosed nor treated. Diagnosis of mood state might be easy in isolated cases yet it often is not since the precise nature of normal mood cannot be expressed in quantitative terms. Furthermore, depression can only be diagnosed based on the doctor's clinical appraisal and the patient's own description of his/her complaints. There is no gold standard on which depressive symptoms can be based on--and further on, depression is not a diagnosis. Instead, it is a syndrome that calls for differential diagnoses before treatment can be offered. Diagnosing depressive comorbidity in patients with medical complaints is even more difficult because of the overlap between symptoms of depression and accompanying symptoms of the somatic illness e.g. lack of energy. Although depressive states have been known to be a risk factor for the prognosis of patients with coronary heart disease for a long time, there is a paucity of research about the therapy these patients undergo due to the fact that tricyclic anti-depressants can have cardiotoxic effects on patients with heart disease. The treatment of depression in these patients has become a much lower risk since the introduction of serotonin reuptake inhibitors. There is widespread evidence that depressive comorbidity has a negative impact on the prognosis of medical disorders. Despite the complex nature of diagnosing depression, proper diagnosis and treatment is increasingly important in internal medicine and especially cardiology.