Thomas Stocker

Small but mighty: Platelets as central effectors of host defense

Platelets actively participate in inflammatory processes and drive diseases such as atherosclerosis, rheumatoid arthritis and cancer metastasis. However, platelets also have anti-inflammatory and anti-infective properties, which have received less consideration in the past. In this review, we highlight recent findings on the role of platelets in host defense and describe regulatory pathways modulating immune responses. Furthermore, we discuss the role of platelets for the resolution of inflammation and tissue repair. These conceptual changes contribute to our understanding of platelet biology in disease.

Coronin 1A, a novel player in integrin biology, controls neutrophil trafficking in innate immunity

Trafficking of polymorphonuclear neutrophils (PMNs) during inflammation critically depends on the β2 integrins lymphocyte function-associated antigen 1 (LFA-1) (CD11a/CD18) and macrophage-1 antigen (CD11b/CD18). Here, we identify coronin 1A (Coro1A) as a novel regulator of β2 integrins that interacts with the cytoplasmic tail of CD18 and is crucial for induction of PMN adhesion and postadhesion events, including adhesion strengthening, spreading, and migration under flow conditions. Transition of PMN rolling to firm adhesion critically depends on Coro1A by regulating the accumulation of high-affinity LFA-1 in focal zones of adherent cells. Defective integrin affinity regulation in the genetic absence of Coro1A impairs leukocyte adhesion and extravasation in inflamed cremaster muscle venules in comparison with control animals. In a Helicobacter pylori mouse infection model, PMN infiltration into the gastric mucosa is dramatically reduced in Coro1A-/- mice, resulting in an attenuated gastric inflammation. Thus, Coro1A represents an important novel player in integrin biology, with key functions in PMN trafficking during innate immunity.

Rationale and design of the worldwide prospective multicenter registry on radiation dose estimates of cardiac CT angiography in daily practice in 2017 (PROTECTION VI)

BACKGROUND Cardiac computed tomography angiography (cardiac CTA) is an increasingly used versatile imaging method to evaluate coronary and cardiac morphology. Owing to improvements in technology, image quality has continuously improved over the last 10-20 years. At the same time, numerous non-randomized and randomized studies have been performed to reduce the associated radiation exposure. Currently, it is unclear if the advances in technology and knowledge about radiation reduction translated into reduced levels of cardiac CTA radiation dose in daily clinical practice as well as a wide utilization of dose-saving strategies. METHODS The PROTECTION VI study is a multicenter, prospective, worldwide registry designed to evaluate radiation dose exposure, utilization of dose-saving strategies and diagnostic image quality during cardiac CTA in current daily practice. Assessment of image quality will be addressed by the evaluation of diagnostic image quality at the local study site and the calculation of quantitative image quality parameters in an imaging core laboratory. Above 4000 patients will be enrolled from approximately 70 sites in Europe, North America, South America, Asia and Australia. The study will analyze median radiation dose levels, image quality, frequency of use and efficacy of algorithms for dose reduction, and patient and study-related predictors associated with radiation dose. CONCLUSIONS The PROTECTION VI study is designed to provide a reliable estimate of current radiation dose for cardiac CTA and to assess the potential for additional dose reductions.

Cathelicidins prime platelets to mediate arterial thrombosis and tissue inflammation

Leukocyte-released antimicrobial peptides contribute to pathogen elimination and activation of the immune system. Their role in thrombosis is incompletely understood. Here we show that the cathelicidin LL-37 is abundant in thrombi from patients with acute myocardial infarction. Its mouse homologue, CRAMP, is present in mouse arterial thrombi following vascular injury, and derives mainly from circulating neutrophils. Absence of hematopoietic CRAMP in bone marrow chimeric mice reduces platelet recruitment and thrombus formation. Both LL-37 and CRAMP induce platelet activation in vitro by involving glycoprotein VI receptor with downstream signaling through protein tyrosine kinases Src/Syk and phospholipase C. In addition to acute thrombosis, LL-37/CRAMP-dependent platelet activation fosters platelet–neutrophil interactions in other inflammatory conditions by modulating the recruitment and extravasation of neutrophils into tissues. Absence of CRAMP abrogates acid-induced lung injury, a mouse pneumonia model that is dependent on platelet–neutrophil interactions. We suggest that LL-37/CRAMP represents an important mediator of platelet activation and thrombo-inflammation.Cathelicidins are antimicrobial peptides that eliminate pathogens and contribute to the innate immune response. Here the authors show that neutrophil-derived LL-37/CRAMP induces platelet activation and promotes arterial thrombosis and thrombo-inflammation.

ACUTE AND SHORT-TERM RESULTS OF TRANSCATHETER TREATMENT OF SEVERE TRICUSPID REGURGITATION USING THE EDGE-TO-EDGE REPAIR SYSTEM

Tricuspid regurgitation (TR) is associated with significant morbidity and mortality. There is a clinical need for interventional treatment strategies for patients ineligible for cardiac surgery. We evaluated the acute and short-term results of a total of 61 inoperable patients with symptomatic

TRANSCATHETER EDGE-TO-EDGE REPAIR FOR SEVERE TRICUSPID REGURGITATION USING THE TRIPLE ORIFICE VERSUS BICUSPIDALIZATION TECHNIQUE

The edge-to-edge repair technique has been successfully used for patients with severe tricuspid regurgitation (TR). The aim of this analysis was to investigate the optimal treatment strategy using this approach. Tricuspid clip implantation was performed using a modified steering technique. Clips

Impact of diabetes on coronary artery plaque volume by coronary CT angiography and subsequent adverse cardiac events

BACKGROUND To investigate the impact of diabetes on coronary artery total plaque volume (TPV) and adverse events in long-term follow-up. METHODS One-hundred-and-eight diabetic patients were matched to 324 non-diabetic patients, with respect to age, sex, body-mass index, hypertension, smoking habits, LDL and HDL cholesterol, family history for CAD as well as aspirin and statin medication. In all patients, TPV was quantified from coronary CT angiographies (CTA) using dedicated software. All-cause mortality, acute coronary syndrome and late revascularisation (>90 days) served as combined endpoint. RESULTS Patients were followed for 5.6 years. The endpoint occurred in 18 (16.7%) diabetic and 26 (8.0%) non-diabetic patients (odds ratio 2.3, p = 0.03). Diabetic patients had significantly higher TPV than non-diabetic patients (55.1 mm³ [IQR: 6.2 and 220.4 mm³] vs. 24.9 mm³ [IQR: 0 and 166.7 mm³], p = 0.02). A TPV threshold of 110.5 mm³ provided good separation of diabetic and non-diabetic patients at higher and lower risk for adverse events. Noteworthy, diabetic and non-diabetic patients with a TPV<110.5 mm³ had comparable outcome (hazard ratio: 1.3, p = 0.59), while diabetic patients with TPV>110.5 mm³ had significantly higher incidence of adverse events (hazard ratio 2.3, p = 0.03) compared to non-diabetic patients with TPV>110.5 mm³. There was incremental prognostic value in diabetic and non-diabetic patients over the Framingham Risk Score (Integrated Discrimination Improvement: 0.052 and 0.012, p for both <0.05). CONCLUSION Diabetes is associated with significantly higher TPV, which is independent of other CAD risk factors. Quantification of TPV improves the identification of diabetic patients at higher risk for future adverse events.

Physical Activity and Noninvasive Cardiac Output as Novel Clinical Endpoints After Transcatheter Valve Repair for Severe Tricuspid Regurgitation

Tricuspid regurgitation (TR) is an increasingly recognized progressive disease associated with poor quality of life and reduced long-term survival [(1)][1]. A substantial fraction of patients with severe TR are deemed ineligible for surgery because of frailty and comorbidities. This has resulted in

Impairment of Quality of Life among Patients with Wearable Cardioverter Defibrillator Therapy (LifeVest®): A Preliminary Study

Background Wearable cardioverter defibrillator (WCD) therapy is feasible and safe in patients as a transient protection against sudden cardiac death (SCD). However, the impact of WCD therapy on quality of life (QoL) has not been studied. Methods In our single-centre study, 109 consecutive patients with a prescription of WCD were retrospectively analysed. Quality of life has been assessed by a standardized questionnaire (EQ-5D-3L, modified). Additionally, clinical baseline and follow-up data and recorded arrhythmic episodes were evaluated. Results Mean WCD therapy time was 56.2 (± 42.4) days, with a daily wear time of 19.7 (± 5) hours. A total of 3441 arrhythmia episodes were detected. Of these, 27 (1%) were adequate but did not require shock therapy. Likewise, no inadequate shock therapy occurred. WCD therapy negatively affected quality of life: 43% of patients reported mental health issues. 37% reported pain or discomfort. Self-care, usual activities, and mobility were restricted in 17%, 48%, and 36%, respectively. 29% were afraid of receiving shock therapy, and 48% suffered from sleep disturbance. However, 64% indicated having felt safe during WCD therapy. Accordingly, average quality of life was rated 70/100 points. Conclusion In our cohort, no SCD was prevented by WCD therapy. In contrast, in this preliminary study quality of life was reduced. Thus, careful recommendation of WCD therapy for high risk patients should be considered.