Erez Kachel

Ex Vivo Activated Human Macrophages Improve Healing, Remodeling, and Function of the Infarcted Heart

Background— Activated macrophages have a significant role in wound healing and damaged tissue repair. We sought to explore the ability of ex vivo activated macrophages to promote healing and repair of the infarcted myocardium. Methods and Results— Human activated macrophage suspension (AMS) was prepared from a whole blood unit obtained from young donors in a closed sterile system and was activated by a novel method of hypo-osmotic shock. The AMS (≈4×105 cells) included up to 43% CD14-positive cells and was injected into the ischemic myocardium of rats (n=8) immediately after coronary artery ligation. The control group (n=9) was treated with saline injection. The human cells existed in the infarcted heart 4 to 7 days after injection, as indicated by histology, human growth hormone-specific polymerase chain reaction, and magnetic resonance imaging (MRI) tracking of iron oxide–nanoparticle-labeled cells. After 5 weeks, scar vessel density (±SE) (25±4 versus 10±1 per mm2; P<0.05), myofibroblast accumulation, and recruitment of resident monocytes and macrophages were greater in AMS-treated hearts compared with controls. Serial echocardiography studies, before and 5 weeks after injection, showed that AMS improved scar thickening (0.15±0.01 versus 0.11±0.01 cm; P<0.05), reduced left ventricular (LV) diastolic dilatation (0.87±0.02 versus 0.99±0.04 cm; P<0.05), and improved LV fractional shortening (31±2 versus 20±4%; P<0.05), compared with controls. Conclusions— Early after myocardial infarction, injection of AMS accelerates vascularization, tissue repair, and improves cardiac remodeling and function. Our work suggests a novel clinically relevant option to promote the repair of ischemic tissue.

Treatment of deep sternal wound infections post-open heart surgery by application of activated macrophage suspension

Postoperative sternal wound infection remains a significant complication and generally causes considerable morbidity and mortality. Macrophages play a major role in the process of wound healing. In order to evaluate the efficacy of local injection of activated macrophage suspensions into open infected sternal wound space, a retrospective case‐control study was conducted. Sixty‐six patients with deep sternal wound infection treated by activated macrophages (group 1) and 64 patients with deep sternal wound infection treated by sternal reconstruction surgery with various regional flaps (group 2), were matched for gender, age, and risk index. In up to 54 months of follow‐up of group 1, 60 patients (91%) achieved complete wound closure. Two (3%) late deaths occurred unrelated to the procedure. Mortality rate in group 2 was 29.7% (19/64). Duration of hospitalization was 22.6 days in group 1 vs. 56.2 days in group 2. Patients with deep sternal wound infection following open heart surgery that were treated by activated macrophages had significantly less mortality as well as significant reduction of hospitalization in comparison to the surgically treated group. These results illustrate the advantages of using a biologically based activated macrophage treatment.

Mitochondrial function and tissue vitality: bench-to-bedside real-time optical monitoring system

BACKGROUND The involvement of mitochondria in pathological states, such as neurodegenerative diseases, sepsis, stroke, and cancer, are well documented. Monitoring of nicotinamide adenine dinucleotide (NADH) fluorescence in vivo as an intracellular oxygen indicator was established in 1950 to 1970 by Britton Chance and collaborators. We use a multiparametric monitoring system enabling assessment of tissue vitality. In order to use this technology in clinical practice, the commercial developed device, the CritiView (CRV), is tested in animal models as well as in patients. METHODS AND RESULTS The new CRV enables the optical monitoring of four different parameters, representing the energy balance of various tissues in vivo. Mitochondrial NADH is measured by surface fluorometry/reflectometry. In addition, tissue microcirculatory blood flow, tissue reflectance and oxygenation are measured as well. The device is tested both in vitro and in vivo in a small animal model and in preliminary clinical trials in patients undergoing vascular or open heart surgery. In patients, the monitoring is started immediately after the insertion of a three-way Foley catheter (urine collection) to the patient and is stopped when the patient is discharged from the operating room. The results show that monitoring the urethral wall vitality provides information in correlation to the surgical procedure performed.

Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling

Background Ascending thoracic aortic aneurysm (ATAA) is driven by angiotensin II (AngII) and contributes to the development of left ventricular (LV) remodeling through aortoventricular coupling. We previously showed that locally available leptin augments AngII‐induced abdominal aortic aneurysms in apolipoprotein E–deficient mice. We hypothesized that locally synthesized leptin mediates AngII‐induced ATAA. Methods and Results Following demonstration of leptin synthesis in samples of human ATAA associated with different etiologies, we modeled in situ leptin expression in apolipoprotein E–deficient mice by applying exogenous leptin on the surface of the ascending aorta. This treatment resulted in local aortic stiffening and dilation, LV hypertrophy, and thickening of aortic/mitral valve leaflets. Similar results were obtained in an AngII‐infusion ATAA mouse model. To test the dependence of AngII‐induced aortic and LV remodeling on leptin activity, a leptin antagonist was applied to the ascending aorta in AngII‐infused mice. Locally applied single low‐dose leptin antagonist moderated AngII‐induced ascending aortic dilation and protected mice from ATAA rupture. Furthermore, LV hypertrophy was attenuated and thickening of aortic valve leaflets was moderated. Last, analysis of human aortic valve stenosis leaflets revealed de novo leptin synthesis, whereas exogenous leptin stimulated proliferation and promoted mineralization of human valve interstitial cells in culture. Conclusions AngII‐induced ATAA is mediated by locally synthesized leptin. Aortoventricular hemodynamic coupling drives LV hypertrophy and promotes early aortic valve lesions, possibly mediated by valvular in situ leptin synthesis. Clinical implementation of local leptin antagonist therapy may attenuate AngII‐induced ATAA and moderate related LV hypertrophy and pre–aortic valve stenosis lesions. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00449306.

Giant Left Atrium Needed Negative Pressure Ventilation

Giant left atrium (GLA) is seen in a variety of cardiac conditions. The GLA is diagnosed by combining the patients history, physical examination, and imaging techniques, along with a computed tomographic chest scan, echocardiogram, and barium swallow test. We recently operated on a severely symptomatic 71-year-old woman with GLA (135 mm x 192 mm). We were forced to anesthetize her with negative pressure ventilation before connecting to the cardiopulmonary bypass circuit. Her postoperative course and long-term follow-up were uneventful. The procedure for GLA reduction is safe, even in very high-risk patients. Negative pressure ventilation may be used successfully as a bridge to cardiopulmonary bypass in certain cases.

MEFV mutation carriage as possible predisposition factor for the development of Post Pericardiotomy Syndrome (PPS)

Methods 86 patients who underwent cardiac surgery were studied, 45 of whom developed PPS (study group) and 41 have not (control group). Demographic data (gender, age, region of residence, ethnic origin) and type of surgery were collected. The severity of PPS was evaluated, based on a predefined scale. Genetic analysis determining carriage of one of the three most common MEFV gene mutations (M694V, V726A, E148Q) was performed.