Henrik Fox

MicroRNA-92a Controls Angiogenesis and Functional Recovery of Ischemic Tissues in Mice

Of Life, Limb, and a Small RNA Gene expression in mammals is controlled not only by proteins but by small noncoding RNAs called microRNAs. The involvement of these RNAs provides powerful clues about the molecular origins of human diseases and how they might be treated. Ischemic diseases arise from an inadequate blood supply. Bonauer et al. (p. 1710, published online 21 May) find that a specific microRNA that is expressed in the cells lining blood vessels (called miR-92a) functions to repress the growth of new blood vessels. MiR-92a probably acts through effects on expression of integrins, proteins involved in cell adhesion and migration. In mouse models in which an inadequate blood supply had caused damage either to heart or limb muscle, therapeutic inhibition of miR-92a led to an increase in blood vessel density in the damaged tissues and enhanced functional recovery. Inhibition of a microRNA that represses blood vessel growth enhances the recovery of tissue damaged by an inadequate blood supply. MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression by binding to target messenger RNAs (mRNAs), leading to translational repression or degradation. Here, we show that the miR-17~92 cluster is highly expressed in human endothelial cells and that miR-92a, a component of this cluster, controls the growth of new blood vessels (angiogenesis). Forced overexpression of miR-92a in endothelial cells blocked angiogenesis in vitro and in vivo. In mouse models of limb ischemia and myocardial infarction, systemic administration of an antagomir designed to inhibit miR-92a led to enhanced blood vessel growth and functional recovery of damaged tissue. MiR-92a appears to target mRNAs corresponding to several proangiogenic proteins, including the integrin subunit alpha5. Thus, miR-92a may serve as a valuable therapeutic target in the setting of ischemic disease.

Circulating MicroRNAs in Patients With Coronary Artery Disease

Rationale: MicroRNAs are small RNAs that control gene expression. Besides their cell intrinsic function, recent studies reported that microRNAs are released by cultured cells and can be detected in the blood. Objective: To address the regulation of circulating microRNAs in patients with stable coronary artery disease. Methods and Results: To determine the regulation of microRNAs, we performed a microRNA profile using RNA isolated from n=8 healthy volunteers and n=8 patients with stable coronary artery disease that received state-of-the-art pharmacological treatment. Interestingly, most of the highly expressed microRNAs that were lower in the blood of patients with coronary artery disease are known to be expressed in endothelial cells (eg, miR-126 and members of the miR-17∼92 cluster). To prospectively confirm these data, we detected selected microRNAs in plasma of 36 patients with coronary artery disease and 17 healthy volunteers by quantitative PCR. Consistent with the data obtained by the profile, circulating levels of miR-126, miR-17, miR-92a, and the inflammation-associated miR-155 were significantly reduced in patients with coronary artery disease compared with healthy controls. Likewise, the smooth muscle–enriched miR-145 was significantly reduced. In contrast, cardiac muscle–enriched microRNAs (miR-133a, miR-208a) tend to be higher in patients with coronary artery disease. These results were validated in a second cohort of 31 patients with documented coronary artery disease and 14 controls. Conclusions: Circulating levels of vascular and inflammation-associated microRNAs are significantly downregulated in patients with coronary artery disease.

CXCR4 Expression Determines Functional Activity of Bone Marrow–Derived Mononuclear Cells for Therapeutic Neovascularization in Acute Ischemia

Objective—Bone marrow–derived mononuclear cells (BMCs) improve the functional recovery after ischemia. However, BMCs comprise a heterogeneous mixture of cells, and it is not known which cell types are responsible for the induction of neovascularization after cell therapy. Because cell recruitment is critically dependent on the expression of the SDF-1-receptor CXCR4, we examined whether the expression of CXCR4 may identify a therapeutically active population of BMCs. Methods and Results—Human CXCR4+ and CXCR4− BMCs were sorted by magnetic beads. CXCR4+ BMCs showed a significantly higher invasion capacity under basal conditions and after SDF-1 stimulation. Hematopoietic or mesenchymal colony-forming capacity did not differ between CXCR4+ and CXCR4− BMCs. Injection of CXCR4+ BMCs in mice after induction of hindlimb ischemia significantly improved the recovery of perfusion compared to injection of CXCR4− BMCs. Likewise, capillary density was significantly increased in CXCR4+ BMC-treated mice. Because part of the beneficial effects of cell therapy were attributed to the release of paracrine effectors, we analyzed BMC supernatants for secreted factors. Importantly, supernatants of CXCR4+ BMCs were enriched in the proangiogenic cytokines HGF and PDGF-BB. Conclusion—CXCR4+ BMCs exhibit an increased therapeutic potential for blood flow recovery after acute ischemia. Mechanistically, their higher migratory capacity and their increased release of paracrine factors may contribute to enhanced tissue repair.

The STS score is the strongest predictor of long-term survival following transcatheter aortic valve implantation, whereas access route (transapical versus transfemoral) has no predictive value beyond the periprocedural phase

OBJECTIVES Transcatheter aortic valve implantation (TAVI) was developed as a promising new therapy for inoperable and surgical high-risk patients as an alternative to traditional aortic valve replacement. After a successful procedure, prognosis may mainly be determined by comorbidities. However, no appropriate risk score to predict long-term outcome following TAVI is currently available. The aim of this study was to identify predictors of adverse short- and long-term outcomes. METHODS This is a two-centre registry study including a total of 426 TAVI procedures (274 transfemoral [TF] and 152 transapical [TA]) performed at the University Hospital and CardioVascular Center of Frankfurt (Germany) between 2005 and 2011. RESULTS Observed 30-day mortality was 4.8% among TF and 12.6% among TA patients (hazard ratio [HR] TF vs TA was 0.38; 95% confidence interval [CI] 0.19-0.77). Patients with a higher Society of Thoracic Surgeons (STS) score experienced a 6% elevation in the 30-day mortality per point (HR 1.06; 95% CI 1.03-1.10), whereas the predictive value of the logistic EuroSCORE (HR 1.03; 95% CI 1.01-1.05) and EuroSCORE 2 (HR 1.04; 95% CI 1.01-1.07) was slightly lower. Most interestingly, older age (>80 years) and the access type were predictors of 30-day mortality. However, the only independent predictor of long-term mortality in a 30-day landmark analysis was the STS score (HR 1.05; 95% CI 1.02-1.09). CONCLUSIONS The STS score outperforms the logistic EuroSCORE in predicting adverse outcomes following TAVI. The transapical approach is associated with higher perioperative mortality, but does not exert any influence on long-term prognosis beyond the periprocedural phase.

Transcatheter aortic valve implantation improves outcome compared to open-heart surgery in kidney transplant recipients requiring aortic valve replacement

BACKGROUND Cardiovascular disease is the most frequent cause of mortality for kidney transplant recipients. Open heart surgery has particularly high mortality and morbidity. As an alternative to traditional aortic valve replacement (AVR) for patients with high-grade aortic stenosis, transcatheter aortic valve implantation (TAVI) was developed as an innovative therapy for patients considered at high surgical risk. METHODS We considered all kidney transplant recipients as high-risk patients, which are candidates for TAVI. In 2010 and 2011, eight kidney transplant recipients with severe aortic stenosis underwent TAVI (6 transfemoral; 2 transapical; group I). The outcome of these patients was compared retrospectively to 18 kidney transplant recipients with aortic stenosis, who underwent conventional AVR (group II). RESULTS Both groups had similar baseline characteristics, including estimated perioperative risk (EuroSCORE group I vs. group II: 9.5±5.9 vs. 10.4±10.5; p=0.829). All TAVI procedures were performed successfully with excellent functional results. In the TAVI group (group I), all patients were alive at the 12-month follow-up with one cardiovascular event (stroke). In contrast, the surgical group experienced a 30-day-mortality of 11.1% (n=2) and a 1-year-mortality of 16.7% (n=3). CONCLUSIONS Based on our centers experience, TAVI appears to be an effective and safe alternative to conventional surgery for AVR in patients with prior renal transplantation. Renal transplantation is not currently identified as a risk factor in our traditional scoring system, and may need to be considered independently when weighing alternatives for AVR.

Venoarterielle ECMO als „bridge to recovery“

We report a case of a 37-year-old patient presenting with fulminant cardiogenic shock, almost noncontractile ventricles, followed by electromechanical dissociation. During performance of cardiopulmonary resuscitation, a veno-arterial extracorporeal membrane oxygenation device (VA ECMO) was implanted, which became necessary for 13 days. Subsequently, a total arrest of ventricular function was observed and prominent multiple organ failure emerged. A rapid test for respiratory syncytial virus was positive, supporting the suspected diagnosis of myocarditis. Despite numerous complications, complete recovery was achieved.

UTILITY OF CONVENTIONAL SURGICAL RISK SCORES IN PREDICTING OUTCOME AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT

Models to predict outcome after TAVI have not been designed or validated. The performance of surgical risk scores for TAVI has not been assessed. We aimed to examine the utility of the Society of Thoracic Surgeons (STS) risk score, logistic European System for Cardiac Risk Evaluation score (log

Extensive dissecting aneurysm of the ascending aorta

We present the case of a 69-year-old female surviving an extensive dissecting thoracic aortic aneurysm. Due to the initial presentation with angina and epigastric pain the first working diagnosis was acute coronary syndrome. However, on transthoracic and transesophageal echocardiography (TEE), the dissecting aneurysm (type Stanford A) could be detected. Our article stresses the importance of imaging for the rapid and accurate diagnosis of thoracic aortic aneurysms with dissection. In our case, TEE detected the intimal flap separating true and false lumen, and the consecutive hemodynamically relevant aortic valve regurgitation, in addition to the aneurysm extent. The patient underwent surgical repair with aortic arch replacement and recovered without sequelae. <Learning objective: In patients with severe hypertension and coronary artery disease presenting with atypical chest pain, ECG and troponin T assessment should be complemented by imaging of the heart and the ascending aorta to rule out aortic dissection.>.

Safety and feasibility of transcatheter aortic valve implantation in patients with severe persistent thrombocytopenia.

Untreated symptomatic high-grade aortic stenosis remains a lethal disease. Therefore, a comprehensive evaluation is necessary to obtain the best individual treatment for each patient. Recently, transcatheter aortic valve implantation (TAVI) was developed as an innovative therapy for high-risk and inoperable patients. Persistent thrombocytopenia is an established risk for conventional open heart surgery, but is not covered by traditional surgical risk scores. The aim of the study was the investigation of safety and feasibility of TAVI in patients with severe thrombocytopenia. Because of the complicated outcome of patients with persistent thrombocytopenia undergoing heart surgery, we considered all patients with high-grade aortic stenosis and a thrombocyte count of less than 100 per nl as surgical high-risk patients. Out of these high-risk surgical patients, six patients with symptomatic high-grade aortic stenosis and severe thrombocytopenia were deemed to be TAVI candidates and underwent TAVI procedures in 2010 and 2011 (transfemoral: n = 4; transapical: n = 2) at the University Hospital of Frankfurt. The outcome of these patients was analyzed prospectively in order to document safety and feasibility of TAVI in such patients. All TAVI procedures were performed successfully with excellent functional results. There was no occurrence of major or minor bleeding complications, acute renal failure or nosocomial infection. One patient died of an ischemic stroke 12 days after the procedure. The five remaining patients were alive at the 12-month follow-up without relevant cardiovascular events and excellent valve performance. TAVI is an effective and well tolerated method to treat patients with chronic persistent thrombocytopenia and symptomatic high-grade aortic stenosis, and therefore a reasonable alternative to conventional heart surgery in such patients. The indication for TAVI in patients with thrombocytopenia and symptomatic high-grade aortic stenosis might be generated independently from conventional scoring systems.

Venoarterielle ECMO als „bridge to recovery“@@@Veno-arterial ECMO as bridge to recovery: Kardiogener Schock und Verdacht auf Myokarditis bei einer 37-Jährigen@@@Cardiogenic shock and suspected myocarditis in a 37-year-old patient

We report a case of a 37-year-old patient presenting with fulminant cardiogenic shock, almost noncontractile ventricles, followed by electromechanical dissociation. During performance of cardiopulmonary resuscitation, a veno-arterial extracorporeal membrane oxygenation device (VA ECMO) was implanted, which became necessary for 13 days. Subsequently, a total arrest of ventricular function was observed and prominent multiple organ failure emerged. A rapid test for respiratory syncytial virus was positive, supporting the suspected diagnosis of myocarditis. Despite numerous complications, complete recovery was achieved.