Sterile Abscess in the Myocardium after Direct Intramyocardial Injection Related to Gene Therapy in a Swine Model

Cardiac gene therapy is one of the most promising approaches to cure patients with cardiac dysfunctions. Many ways of efficient gene transfer using viral vectors are tested, and some of them are already used in clinical settings. However, it is always important to be keenly alert to the possible complications when a new therapy is introduced. We present a case of myocardial sterile abscess in a swine model associated with a direct myocardial injection

AAV9.I-1c Delivered via Direct Coronary Infusion in a Porcine Model of Heart Failure Improves Contractility and Mitigates Adverse Remodeling

Heart failure is characterised by impaired function and disturbed Ca2+ homeostasis. Transgenic increases in inhibitor-1 activity have been shown to improve Ca2 cycling and preserve cardiac performance in the failing heart. The aim of this study is to evaluate the effect of activating the inhibitor (I-1c) of protein phosphatase 1 (I-1) through gene transfer on cardiac function in a porcine model of heart failure induced by myocardial infarction (MI)

Cardiac I-1c Overexpression With Reengineered AAV Improves Cardiac Function in Swine Ischemic Heart Failure

Cardiac gene therapy has emerged as a promising option to treat advanced heart failure (HF). Advances in molecular biology and gene targeting approaches are offering further novel options for genetic manipulation of the cardiovascular system. The aim of this study was to improve cardiac function in chronic HF by overexpressing constitutively active inhibitor-1 (I-1c) using a novel cardiotropic vector generated by capsid reengineering of adeno-associated virus (BNP116). One month after a large anterior myocardial infarction, 20 Yorkshire pigs randomly received intracoronary injection of either high-dose BNP116.I-1c (1.0 × 1013 vector genomes (vg), n = 7), low-dose BNP116.I-1c (3.0 × 1012 vg, n = 7), or saline (n = 6). Compared to baseline, mean left ventricular ejection fraction increased by 5.7% in the high-dose group, and by 5.2% in the low-dose group, whereas it decreased by 7% in the saline group. Additionally, preload-recruitable stroke work obtained from pressure–volume analysis demonstrated significantly higher cardiac performance in the high-dose group. Likewise, other hemodynamic parameters, including stroke volume and contractility index indicated improved cardiac function after the I-1c gene transfer. Furthermore, BNP116 showed a favorable gene expression pattern for targeting the heart. In summary, I-1c overexpression using BNP116 improves cardiac function in a clinically relevant model of ischemic HF

Implantation of vascular mimetic implants in challenging chronic total occlusions – Supera^TM Extreme

Summary: Standard nitinol stents (SNS), with or without drug eluting technology, are an essential tool within the interventional armamentarium in the treatment of patients with peripheral arterial disease. However, they are plagued by a number of limitations: a.) stent fractures, although observed predominately in first-generation stents, do still occur in state-of-the art stent platforms, b.) lack of radial strength, resulting in inadequate stent expansion, c.) kinking up to a complete collapse of the stent, therefore compromising its use in areas of high mechanical stress such as bending zones. In contrast, the interwoven design of the SuperaTM stent, also referred to as “vascular mimetic implant”, overcomes all of the above limitations of SNS. Several registries and studies not only confirmed its mechanical superiority (lack of stent fractures etc.) but also demonstrated remarkable clinical performance (patency and freedom from target lesion revascularization), despite its use in challenging lesions (calcification etc.) and territories (popliteal arteries etc.). Increasing confidence in the mechanical properties of the SuperaTM stent platform prompted interventionalists to further “push the limits” of this unique implant. The present article summarizes the clinical data and shows examples of “extreme” applications of this dedicated stent platform. </jats:p

Gene Therapy for Heart Failure

Congestive heart failure accounts for half a million deaths per year in the United States. Despite its place among the leading causes of morbidity, pharmacological and mechanic remedies have only been able to slow the progression of the disease. Today's science has yet to provide a cure, and there are few therapeutic modalities available for patients with advanced heart failure. There is a critical need to explore new therapeutic approaches in heart failure, and gene therapy has emerged as a viable alternative. Recent advances in understanding of the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed heart failure within reach of gene-based therapy. The recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a), along with the start of more recent phase 1 trials, opens a new era for gene therapy for the treatment of heart failure.</jats:p

Diagnostic accuracy of spirometry in primary care.

Contains fulltext : 80404.pdf (publisher's version ) (Open Access)BACKGROUND: To evaluate the sensitivity, specificity and predictive values of spirometry for the diagnosis of chronic obstructive pulmonary disease (COPD) and asthma in patients suspected of suffering from an obstructive airway disease (OAD) in primary care. METHODS: Cross sectional diagnostic study of 219 adult patients attending 10 general practices for the first time with complaints suspicious for OAD. All patients underwent spirometry and structured medical histories were documented. All patients received whole-body plethysmography (WBP) in a lung function laboratory. The reference standard was the Tiffeneau ratio (FEV1/VC) received by the spirometric maneuver during examination with WBP. In the event of inconclusive results, bronchial provocation was performed to determine bronchial hyper-responsiveness (BHR). Asthma was defined as a PC20 fall after inhaling methacholine concentration < or = 16 mg/ml. RESULTS: 90 (41.1%) patients suffered from asthma, 50 (22.8%) suffered from COPD, 79 (36.1%) had no OAD. The sensitivity for diagnosing airway obstruction in COPD was 92% (95%CI 80-97); specificity was 84% (95%CI 77-89). The positive predictive value (PPV) was 63% (95%CI 51-73); negative predictive value (NPV) was 97% (95%CI 93-99). The sensitivity for diagnosing airway obstruction in asthma was 29% (95%CI 21-39); specificity was 90% (95%CI 81-95). PPV was 77% (95%CI 60-88); NPV was 53% (95%CI 45-61). CONCLUSION: COPD can be estimated with high diagnostic accuracy using spirometry. It is also possible to rule in asthma with spirometry. However, asthma can not be ruled out only using spirometry. This diagnostic uncertainty leads to an overestimation of asthma presence. Patients with inconclusive spirometric results should be referred for nitric oxide (NO) - measurement and/or bronchial provocation if possible to guarantee accurate diagnosis