Handling high-risk patients in the catheterization laboratory.

Protected percutaneous coronary intervention is considered a life-saving procedure for high-risk patients. Therefore it is important that the interventional cardiology team is prepared, the procedure is planned, and potential complications, as well as bail out strategies are considered. Throughout the procedure, it is critical to monitor the patient to identify any early signs of deterioration or changes in patient well-being to avoid any potential complications.

Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome.

BACKGROUND: Cardiogenic shock (CS) and low cardiac output syndrome (LCOS) are potentially life-threatening complications of acute myocardial infarction (AMI), heart failure (HF) or cardiac surgery. While there is solid evidence for the treatment of other cardiovascular diseases of acute onset, treatment strategies in haemodynamic instability due to CS and LCOS remains less robustly supported by the given scientific literature. Therefore, we have analysed the current body of evidence for the treatment of CS or LCOS with inotropic and/or vasodilating agents. This is the second update of a Cochrane review originally published in 2014. OBJECTIVES: Assessment of efficacy and safety of cardiac care with positive inotropic agents and vasodilator agents in CS or LCOS due to AMI, HF or after cardiac surgery. SEARCH METHODS: We conducted a search in CENTRAL, MEDLINE, Embase and CPCI-S Web of Science in October 2019. We also searched four registers of ongoing trials and scanned reference lists and contacted experts in the field to obtain further information. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials (RCTs) enrolling patients with AMI, HF or cardiac surgery complicated by CS or LCOS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures according to Cochrane standards. MAIN RESULTS: We identified 19 eligible studies including 2385 individuals (mean or median age range 56 to 73 years) and three ongoing studies. We categorised studies into 11 comparisons, all against standard cardiac care and additional other drugs or placebo. These comparisons investigated the efficacy of levosimendan versus dobutamine, enoximone or placebo; enoximone versus dobutamine, piroximone or epinephrine-nitroglycerine; epinephrine versus norepinephrine or norepinephrine-dobutamine; dopexamine versus dopamine; milrinone versus dobutamine and dopamine-milrinone versus dopamine-dobutamine. All trials were published in peer-reviewed journals, and analyses were done by the intention-to-treat (ITT) principle. Eighteen of 19 trials were small with only a few included participants. An acknowledgement of funding by the pharmaceutical industry or missing conflict of interest statements occurred in nine of 19 trials. In general, confidence in the results of analysed studies was reduced due to relevant study limitations (risk of bias), imprecision or indirectness. Domains of concern, which showed a high risk in more than 50% of included studies, encompassed performance bias (blinding of participants and personnel) and bias affecting the quality of evidence on adverse events. All comparisons revealed uncertainty on the effect of inotropic/vasodilating drugs on all-cause mortality with a low to very low quality of evidence. In detail, the findings were: levosimendan versus dobutamine (short-term mortality: RR 0.60, 95% CI 0.36 to 1.03; participants = 1701; low-quality evidence; long-term mortality: RR 0.84, 95% CI 0.63 to 1.13; participants = 1591; low-quality evidence); levosimendan versus placebo (short-term mortality: no data available; long-term mortality: RR 0.55, 95% CI 0.16 to 1.90; participants = 55; very low-quality evidence); levosimendan versus enoximone (short-term mortality: RR 0.50, 0.22 to 1.14; participants = 32; very low-quality evidence; long-term mortality: no data available); epinephrine versus norepinephrine-dobutamine (short-term mortality: RR 1.25; 95% CI 0.41 to 3.77; participants = 30; very low-quality evidence; long-term mortality: no data available); dopexamine versus dopamine (short-term mortality: no deaths in either intervention arm; participants = 70; very low-quality evidence; long-term mortality: no data available); enoximone versus dobutamine (short-term mortality RR 0.21; 95% CI 0.01 to 4.11; participants = 27; very low-quality evidence; long-term mortality: no data available); epinephrine versus norepinephrine (short-term mortality: RR 1.81, 0.89 to 3.68; participants = 57; very low-quality evidence; long-term mortality: no data available); and dopamine-milrinone versus dopamine-dobutamine (short-term mortality: RR 1.0, 95% CI 0.34 to 2.93; participants = 20; very low-quality evidence; long-term mortality: no data available). No information regarding all-cause mortality were available for the comparisons milrinone versus dobutamine, enoximone versus piroximone and enoximone versus epinephrine-nitroglycerine. AUTHORS' CONCLUSIONS: At present, there are no convincing data supporting any specific inotropic or vasodilating therapy to reduce mortality in haemodynamically unstable patients with CS or LCOS. Considering the limited evidence derived from the present data due to a high risk of bias and imprecision, it should be emphasised that there is an unmet need for large-scale, well-designed randomised trials on this topic to close the gap between daily practice in critical care of cardiovascular patients and the available evidence. In light of the uncertainties in the field, partially due to the underlying methodological flaws in existing studies, future RCTs should be carefully designed to potentially overcome given limitations and ultimately define the role of inotropic agents and vasodilator strategies in CS and LCOS.

Enhanced potency of cell-based therapy for ischemic tissue repair using an injectable bioactive epitope presenting nanofiber support matrix.

The translation of cell-based therapies for ischemic tissue repair remains limited by several factors, including poor cell survival and limited target site retention. Advances in nanotechnology enable the development of specifically designed delivery matrices to address these limitations and thereby improve the efficacy of cell-based therapies. Given the relevance of integrin signaling for cellular homeostasis, we developed an injectable, bioactive peptide-based nanofiber matrix that presents an integrin-binding epitope derived from fibronectin, and evaluated its feasibility as a supportive artificial matrix for bone marrow-derived pro-angiogenic cells (BMPACs) used as a therapy in ischemic tissue repair. Incubation of BMPACs with these peptide nanofibers in vitro significantly attenuated apoptosis while enhancing proliferation and adhesion. Pro-angiogenic function was enhanced, as cells readily formed tubes. These effects were, in part, mediated via p38, and p44/p42 MAP kinases, which are downstream pathways of focal adhesion kinase. In a murine model of hind limb ischemia, an intramuscular injection of BMPACs within this bioactive peptide nanofiber matrix resulted in greater retention of cells, enhanced capillary density, increased limb perfusion, reduced necrosis/amputation, and preserved function of the ischemic limb compared to treatment with cells alone. This self-assembling, bioactive peptide nanofiber matrix presenting an integrin-binding domain of fibronectin improves regenerative efficacy of cell-based strategies in ischemic tissue by enhancing cell survival, retention, and reparative functions.

CXC-chemokine receptor 4 antagonist AMD3100 promotes cardiac functional recovery after ischemia/reperfusion injury via endothelial nitric oxide synthase-dependent mechanism.

BACKGROUND: CXC-chemokine receptor 4 (CXCR4) regulates the retention of stem/progenitor cells in the bone marrow (BM), and the CXCR4 antagonist AMD3100 improves recovery from coronary ligation injury by mobilizing stem/progenitor cells from the BM to the peripheral blood. Thus, we investigated whether AMD3100 also improves recovery from ischemia/reperfusion injury, which more closely mimics myocardial infarction in patients, because blood flow is only temporarily obstructed. METHODS AND RESULTS: Mice were treated with single subcutaneous injections of AMD3100 (5 mg/kg) or saline after ischemia/reperfusion injury. Three days later, histological measurements of the ratio of infarct area to area at risk were smaller in AMD3100-treated mice than in mice administered saline, and echocardiographic measurements of left ventricular function were greater in the AMD3100-treated mice at week 4. CXCR4(+) cells were mobilized for just 1 day in both groups, but the mobilization of sca1(+)/flk1(+) cells endured for 7 days in AMD3100-treated mice compared with just 1 day in the saline-treated mice. AMD3100 upregulated BM levels of endothelial nitric oxide synthase (eNOS) and 2 targets of eNOS signaling, matrix metalloproteinase-9 and soluble Kit ligand. Furthermore, the loss of BM eNOS expression abolished the benefit of AMD3100 on sca1(+)/flk1(+) cell mobilization without altering the mobilization of CXCR4(+) cells, and the cardioprotective effects of AMD3100 were retained in eNOS-knockout mice that had been transplanted with BM from wild-type mice but not in wild-type mice with eNOS-knockout BM. CONCLUSIONS: AMD3100 prolongs BM progenitor mobilization and improves recovery from ischemia/reperfusion injury, and these benefits appear to occur through a previously unidentified link between AMD3100 and BM eNOS expression.

Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair.

There is great demand for the development of novel therapies for ischemic cardiovascular disease, a leading cause of morbidity and mortality worldwide. We report here on the development of a completely synthetic cell-free therapy based on peptide amphiphile nanostructures designed to mimic the activity of VEGF, one of the most potent angiogenic signaling proteins. Following self-assembly of peptide amphiphiles, nanoscale filaments form that display on their surfaces a VEGF-mimetic peptide at high density. The VEGF-mimetic filaments were found to induce phosphorylation of VEGF receptors and promote proangiogenic behavior in endothelial cells, indicated by an enhancement in proliferation, survival, and migration in vitro. In a chicken embryo assay, these nanostructures elicited an angiogenic response in the host vasculature. When evaluated in a mouse hind-limb ischemia model, the nanofibers increased tissue perfusion, functional recovery, limb salvage, and treadmill endurance compared to controls, which included the VEGF-mimetic peptide alone. Immunohistological evidence also demonstrated an increase in the density of microcirculation in the ischemic hind limb, suggesting the mechanism of efficacy of this promising potential therapy is linked to the enhanced microcirculatory angiogenesis that results from treatment with these polyvalent VEGF-mimetic nanofibers.

Left ventricular structure and function following renal sympathetic denervation in patients with HFpEF: an echocardiographic 9-year long-term follow-up.

Background: High blood pressure is a major risk factor for cardiac remodeling and left ventricular hypertrophy, increasing cardiovascular risk and leading to heart failure with preserved ejection fraction (HFpEF). Since renal sympathetic denervation (RDN) reduces blood pressure in the long term, we aimed to investigate the long-term effect of RDN in patients with HFpEF in the present analysis. Methods: Patients previously enrolled in a local RDN registry who underwent high-frequency RDN with the use of the Symplicity Flex® renal denervation system between 2011 and 2014 were followed up. The patients were assessed by 24-h ambulatory blood pressure measurement, transthoracic echocardiography, and laboratory tests. We used the echocardiographic and biomarker criteria of the Heart Failure Association (HFA)-PEFF (Pre-test assessment, Echocardiography and Natriuretic Peptide Score, Funkctional testing, and Final aetiology) score to identify patients with HFpEF. Results: Echocardiographic assessment was available for 70 patients at a 9-year long-term follow-up. Of these patients, 21 had HFpEF according to the HFA-PEFF score. We found a significant reduction of the HFA-PEFF score from 5.48 ± 0.51 points at baseline to 4.33 ± 1.53 points at the 9-year follow-up (P < 0.01). This decrease was due to a greater reduction in morphological and biomarker subcategories [from 1.95 ± 0.22 to 1.43 ± 0.51 points (P < 0.01) and from 1.52 ± 0.52 to 0.90 ± 0.63 points (P < 0.01), respectively] than in the functional one. Morphologically, there was a reduction in left ventricular hypertrophy and left atrial dilation. Conclusions: The present analysis suggests that RDN may lead to a regression of the extent of HFpEF beyond a reduction in blood pressure and thus possibly contribute to an improvement in prognosis. More detailed information will be provided by ongoing randomized sham-controlled trials.

CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction.

We hypothesized that a small molecule CXCR4 antagonist, AMD3100 (AMD), could augment the mobilization of bone marrow (BM)-derived endothelial progenitor cells (EPCs), thereby enhancing neovascularization and functional recovery after myocardial infarction. Single-dose AMD injection administered after the onset of myocardial infarction increased circulating EPC counts and myocardial vascularity, reduced fibrosis, and improved cardiac function and survival. In mice transplanted with traceable BM cells, AMD increased BM-derived cell incorporation in the ischemic border zone. In contrast, continuous infusion of AMD, although increasing EPCs in the circulation, worsened outcome by blocking EPC incorporation. In addition to its effects as a CXCR4 antagonist, AMD also up-regulated VEGF and matrix metalloproteinase 9 (MMP-9) expression, and the benefits of AMD were not observed in the absence of MMP-9 expression in the BM. These findings suggest that AMD3100 preserves cardiac function after myocardial infarction by enhancing BM-EPC-mediated neovascularization, and that these benefits require MMP-9 expression in the BM, but not in the ischemic region. Our results indicate that AMD3100 could be a potentially useful therapy for the treatment of myocardial infarction.

Safety and efficacy of renal sympathetic denervation: a 9-year long-term follow-up of 24-hour ambulatory blood pressure measurements.

Background: Renal sympathetic denervation (RDN) has been shown to lower arterial blood pressure both in the presence and in the absence of antihypertensive medication in an observation period of up to 3 years. However, long-term results beyond 3 years are scarcely reported. Methods: We performed a long-term follow-up on patients who were previously enrolled in a local renal denervation registry and who underwent radiofrequency RDN with the Symplicity Flex® renal denervation system between 2011 and 2014. The patients were assessed to evaluate their renal function by performing 24-hour ambulatory blood pressure measurement (ABPM), recording their medical history, and conducting laboratory tests. Results: Ambulatory blood pressure readings for 24 h were available for 72 patients at long-term follow-up (FU) [9.3 years (IQR: 8.5-10.1)]. We found a significant reduction of ABP from 150.1/86.1 ± 16.9/12.0 mmHg at baseline to 138.3/77.1 ± 16.5/11.1 mmHg at long-term FU (P < 0.001 for both systolic and diastolic ABP). The number of antihypertensive medications used by the patients significantly decreased from 5.4 ± 1.5 at baseline to 4.8 ± 1.6 at long-term FU (P < 0.01). Renal function showed a significant but expected age-associated decrease in the eGFR from 87.8 (IQR: 81.0-100.0) to 72.5 (IQR: 55.8-86.8) ml/min/1.73 m2 (P < 0.01) in patients with an initial eGFR > 60 ml/min/1.73 m2, while a non-significant decrease was observed in patients with an initial eGFR < 60 ml/min/1.73 m2 at long-term FU [56.0 (IQR: 40.9-58.4) vs. 39.0 (IQR: 13.5-56.3) ml/min/1.73 m2]. Conclusions: RDN was accompanied by a long-lasting reduction in blood pressure with a concomitant reduction in antihypertensive medication. No negative effects could be detected, especially with regard to renal function.

[Effect of a 1-day "REBOA course" on the theoretical and practical skills for the prehospital REBOA setting : Experiences from the RIBCAP-HEMS project]. / Effekt eines eintägigen "REBOA-Kurses" auf die theoretischen und praktischen Fähigkeiten zur prähospitalen REBOA-Anlage : Erfahrungen aus dem RIBCAP-HEMS-Projekt.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) represents an endovascular procedure for aortic occlusion. The procedure can be used for temporary hemorrhage control as a bridge until surgical treatment for noncompressible abdominal or pelvic bleeding and to improve coronary and cerebral perfusion pressure during cardiopulmonary resuscitation. The prehospital administration is challenging and currently hardly possible in Germany. In the REBOA in bleeding and cardiac arrest in the prehospital care by helicopter emergency medical service (RIBCAP-HEMS) project, the prehospital use of REBOA will be tested in a feasibility study. This article describes the training course on the procedure in preparation for prehospital use, which was conducted before the start of the aforementioned feasibility study for the emergency physicians and paramedics (HEMS-TC) of the DRF Air Rescue Base in Halle (Saale). The course provided the necessary theoretical and practical skills to apply REBOA in the prehospital setting to patients in extremis in a safe, indications-conform and time-critical manner. The fact that all emergency physicians of the two air ambulances Christoph 84 and Christoph 85 in Halle are specialists in anesthesiology with corresponding experience in the placement of invasive arterial catheters proved to be advantageous. The training course was able to significantly improve the theoretical and practical abilities of the participants. The results of the currently ongoing study must show whether the procedure can be usefully integrated into the prehospital care of patients in extremis.

Stem and progenitor cell-based therapy in ischaemic heart disease: promise, uncertainties, and challenges.

In the absence of effective endogenous repair mechanisms after cardiac injury, cell-based therapies have rapidly emerged as a potential novel therapeutic approach in ischaemic heart disease. After the initial characterization of putative endothelial progenitor cells and their potential to promote cardiac neovascularization and to attenuate ischaemic injury, a decade of intense research has examined several novel approaches to promote cardiac repair in adult life. A variety of adult stem and progenitor cells from different sources have been examined for their potential to promote cardiac repair and regeneration. Although early, small-scale clinical studies underscored the potential effects of cell-based therapy largely by using bone marrow (BM)-derived cells, subsequent randomized-controlled trials have revealed mixed results that might relate, at least in part, to differences in study design and techniques, e.g. differences in patient population, cell sources and preparation, and endpoint selection. Recent meta-analyses have supported the notion that administration of BM-derived cells may improve cardiac function on top of standard therapy. At this stage, further optimization of cell-based therapy is urgently needed, and finally, large-scale clinical trials are required to eventually proof its clinical efficacy with respect to outcomes, i.e. morbidity and mortality. Despite all promises, pending uncertainties and practical limitations attenuate the therapeutic use of stem/progenitor cells for ischaemic heart disease. To advance the field forward, several important aspects need to be addressed in carefully designed studies: comparative studies may allow to discriminate superior cell populations, timing, dosing, priming of cells, and delivery mode for different applications. In order to predict benefit, influencing factors need to be identified with the aim to focus resources and efforts. Local retention and fate of cells in the therapeutic target zone must be improved. Further understanding of regenerative mechanisms will enable optimization at all levels. In this context, cell priming, bionanotechnology, and tissue engineering are emerging tools and may merge into a combined biological approach of ischaemic tissue repair.

Human studies of angiogenic gene therapy.

Despite significant advances in medical, interventional, and surgical therapy for coronary and peripheral arterial disease, the burden of these illnesses remains high. To address this unmet need, the science of therapeutic angiogenesis has been evolving for almost two decades. Early preclinical studies and phase I clinical trials achieved promising results with growth factors administered as recombinant proteins or as single-agent gene therapies, and data accumulated through 10 years of clinical trials indicate that gene therapy has an acceptable safety profile. However, more rigorous phase II and phase III clinical trials have failed to unequivocally demonstrate that angiogenic agents are beneficial under the conditions and in the patients studied to date. Investigators have worked to understand the biology of the vascular system and to incorporate their findings into new treatments for patients with ischemic disease. Recent gene- and cell-therapy trials have demonstrated the bioactivity of several new agents and treatment strategies. Collectively, these observations have renewed interest in the mechanisms of angiogenesis and deepened our understanding of the complexity of vascular regeneration. Gene therapy that incorporates multiple growth factors, approaches that combine cell and gene therapy, and the administration of "master switch" agents that activate numerous downstream pathways are among the credible and plausible steps forward. In this review, we examine the clinical development of angiogenic gene therapy, summarize several of the lessons learned during the conduct of these trials, and suggest how this prior experience may guide the conduct of future preclinical investigations and clinical trials.

The Hedgehog transcription factor Gli3 modulates angiogenesis.

RATIONALE: The Gli transcription factors are mediators of Hedgehog (Hh) signaling and have been shown to play critical roles during embryogenesis. Previously, we have demonstrated that the Hh pathway is reactivated by ischemia in adult mammals, and that this pathway can be stimulated for therapeutic benefit; however, the specific roles of the Gli transcription factors during ischemia-induced Hh signaling have not been elucidated. OBJECTIVE: To investigate the role of Gli3 in ischemic tissue repair. METHODS AND RESULTS: Gli3-haploinsufficient (Gli3(+/-)) mice and their wild-type littermates were physiologically similar in the absence of ischemia; however, histological assessments of capillary density and echocardiographic measurements of left ventricular ejection fractions were reduced in Gli3(+/-) mice compared to wild-type mice after surgically induced myocardial infarction, and fibrosis was increased. Gli3-deficient mice also displayed reduced capillary density after induction of hindlimb ischemia and an impaired angiogenic response to vascular endothelial growth factor in the corneal angiogenesis model. In endothelial cells, adenovirus-mediated overexpression of Gli3 promoted migration (modified Boyden chamber), small interfering RNA-mediated downregulation of Gli3 delayed tube formation (Matrigel), and Western analyses identified increases in Akt phosphorylation, extracellular signal-regulated kinase (ERK)1/2 activation, and c-Fos expression; however, promoter-reporter assays indicated that Gli3 overexpression does not modulate Gli-dependent transcription. Furthermore, the induction of endothelial cell migration by Gli3 was dependent on Akt and ERK1/2 activation. CONCLUSIONS: Collectively, these observations indicate that Gli3 contributes to vessel growth under both ischemic and nonischemic conditions and provide the first evidence that Gli3 regulates angiogenesis and endothelial cell activity in adult mammals.

Artificial Intelligence Identifies an Urgent Need for Peripheral Vascular Intervention by Multiplexing Standard Clinical Parameters.

BACKGROUND: Peripheral artery disease (PAD) is a significant burden, particularly among patients with severe disease requiring invasive treatment. We applied a general Machine Learning (ML) workflow and investigated if a multi-dimensional marker set of standard clinical parameters can identify patients in need of vascular intervention without specialized intra-hospital diagnostics. METHODS: This is a retrospective study involving patients with stable PAD (sPAD, Fontaine Class I and II, n = 38) and unstable PAD (unPAD, Fontaine Class III and IV, n = 18) in need of invasive therapeutic measures. ML algorithms such as Random Forest were utilized to evaluate a matrix consisting of multiple routinely clinically available parameters (age, complete blood count, inflammation, lipid, iron metabolism). RESULTS: ML has enabled a generation of an Artificial Intelligence (AI) PAD score (AI-PAD) that successfully divided sPAD from unPAD patients (high AI-PAD in sPAD, low AI-PAD in unPAD, cutoff at 50 AI-PAD units). Furthermore, the probability score positively coincided with gold-standard intra-hospital mean ankle-brachial index (ABI). CONCLUSION: AI-based tools may be promising to enable the correct identification of patients with unstable PAD by using existing clinical information, thus supplementing clinical decision making. Additional studies in larger prospective cohorts are necessary to determine the usefulness of this approach in comparison to standard diagnostic measures.

Patient delay and benefit of timely reperfusion in ST-segment elevation myocardial infarction.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI), it is unknown how patient delay modulates the beneficial effects of timely reperfusion. AIMS: To assess the prognostic significance of a contact-to-balloon time of less than 90 min on in-hospital mortality in different categories of symptom-onset-to-first-medical-contact (S2C) times. METHODS: A total of 20 005 consecutive patients from the Feedback Intervention and Treatment Times in ST-segment Elevation Myocardial Infarction (FITT-STEMI) programme treated with primary percutaneous coronary intervention (PCI) were included. RESULTS: There were 1554 deaths (7.8%) with a J-shaped relationship between mortality and S2C time. Mortality was 10.0% in patients presenting within 1 hour, and 4.9%, 6.0% and 7.3% in patient groups with longer S2C intervals of 1-2 hours, 2-6 hours and 6-24 hours, respectively. Patients with a short S2C interval of less than 1 hour (S2C<60 min) had the highest survival benefit from timely reperfusion with PCI within 90 min (OR 0.27, 95% CI 0.23 to 0.31, p<0.0001) as compared with the three groups with longer S2C intervals of 1 hour

Sonic hedgehog induces angiogenesis via Rho kinase-dependent signaling in endothelial cells.

The morphogen Sonic hedgehog (Shh) promotes neovascularization in adults by inducing pro-angiogenic cytokine expression in fibroblasts; however, the direct effects of Shh on endothelial cell (EC) function during angiogenesis are unknown. Our findings indicate that Shh promotes capillary morphogenesis (tube length on Matrigel increased to 271+/-50% of the length in untreated cells, p=0.00003), induces EC migration (modified Boyden chamber assay, 191+/-35% of migration in untreated cells, p=0.00009), and increases EC expression of matrix metalloproteinase 9 (MMP-9) and osteopontin (OPN) mRNA (real-time RT-PCR), which are essential for Shh-induced angiogenesis both in vitro and in vivo. Shh activity in ECs is mediated by Rho, rather than through the "classic" Shh signaling pathway, which involves the Gli transcription factors. The Rho dependence of Shh-induced EC angiogenic activity was documented both in vitro, with dominant-negative RhoA and Rho kinase (ROCK) constructs, and in vivo, with the ROCK inhibitor Y27632 in the mouse corneal angiogenesis model. Finally, experiments performed in MMP-9- and OPN-knockout mice confirmed the roles of the ROCK downstream targets MMP-9 and OPN in Shh-induced angiogenesis. Collectively, our results identify a "nonclassical" pathway by which Shh directly modulates EC phenotype and angiogenic activity.

Role of endothelial progenitor cells during ischemia-induced vasculogenesis and collateral formation.

Cell-based therapy has emerged as a promising therapeutic tool for treatment of ischemic cardiovascular disease. Both unselected bone marrow-derived mononuclear cells (BMNCs), which include stem/progenitor cells and several other cell types, and endothelial progenitor cells (EPCs), a subpopulation of BMNCs, display regenerative potential in ischemic tissue. Abundant evidence supports the involvement of EPCs in capillary growth, and EPCs also appear to participate in the formation of collateral vessels. Collectively, these effects have led to improved perfusion and functional recovery in animal models of myocardial and peripheral ischemia, and in early clinical trials, the therapeutic administration of EPCs to patients with myocardial infarction or chronic angina has been associated with positive trends in perfusion. EPCs also contribute to endothelial repair and may, consequently, impede the development or progression of arteriosclerosis. This review provides a brief summary of the preclinical and clinical evidence for the role of EPCs in blood-vessel formation and repair during ischemic cardiovascular disease.

Mortality in patients with cardiogenic shock treated with the Impella CP microaxial pump for isolated left ventricular failure.

AIMS: Cardiogenic shock is still associated with high mortality rates of around 50%. Intra-aortic counterpulsation had been frequently used in cardiogenic shock, but was previously found to provide no mortality benefit. We investigated the effect of an interdisciplinary and multiprofessional routine strategy of early invasive haemodynamic support in combination with complete revascularization in patients with cardiogenic shock before admission to our intensive care unit. METHODS AND RESULTS: We analysed all cardiogenic shock patients (mean age 62±13 years) presenting at our institution between 2013 and mid 2016, who received an Impella CP microaxial pump for isolated left ventricle support (n=61). Sixty-one per cent (n=37) had been resuscitated before Impella insertion. Overall mortality was 48% (n=29/61) at 30 days. Thirty-day mortality was higher in resuscitated patients (resuscitated: 65% (n=24/37); non-resuscitated: 21% (n=5/24)). When applying the inclusion/exclusion criteria of the SHOCK-II trial, eligible patients (n=25) had a markedly lower mortality (24% (n=6/25) at 30 days) compared with the published trial (~40% in both arms). The observed mortality of SHOCK-II-like patients in the registry was also lower compared with their predicted mortality using IABP-Shock II score (49%) and CardShock score (36%). CONCLUSION: The results of this registry suggest that using a standardized protocol including early active haemodynamic support with Impella CP in cardiogenic shock in patients with isolated left ventricle failure may be associated with improved outcomes and lower than previously reported or predicted mortality rates. Pre-implantation cardiac arrest critically influences observed mortality. The results support the case for a randomized trial.

Early Escalation of Mechanical Circulatory Support Stabilizes and Potentially Rescues Patients in Refractory Cardiogenic Shock.

BACKGROUND: Limited progress has been made in the management of cardiogenic shock (CS). Morbidity and mortality of refractory CS remain high. The effects of mechanical circulatory support (MCS) are promising, although many aspects are elusive. We evaluated efficacy and safety of early combined MCS (Impella microaxial pump + venoarterial extracorporeal membrane oxygenation [VA-ECMO]) in refractory CS and aimed to determine factors for decision-making in combined MCS. METHODS AND RESULTS: We analyzed 69 consecutive patients with refractory CS from our registry requiring combined MCS. In 12 cases, therapy was actively withdrawn according to patient's will. Patients were severely sick (Survival After Venoarterial ECMO score mean±SD, -8.9±4.4) predicting 30% in-hospital survival; ventilation 94%, dialysis 56%. Impella pumps and VA-ECMO were combined early (duration of combined MCS: median 94 hours; interquartile range, 49-150 hours). Early MCS escalation stabilized patients rapidly, reducing number and doses of catecholamines (P<0.05 versus baseline) while hemodynamics improved. Reflecting an improved microcirculation, lactate levels normalized within 24 hours (P<0.05 versus baseline). Despite refractory CS and disease severity, survival was favorable (on MCS 61%, 30 days 49%, 6 months 40%). In multivariate Cox-regression, duration of shock-to-first device (hours, hazard ratio, 1.05 [95% CI, 1.01-1.08]; P=0.007) and lactate levels after 12 hours of MCS (hazard ratio, 1.28 [95% CI, 1.09-1.51]; P=0.002) independently predicted survival. Additional right ventricular failure predisposed to futility (hazard ratio, 8.48 [95% CI, 1.85-38.91]; P=0.006). CONCLUSIONS: The early and consequent combination of MCS by Impella microaxial pumps and VA-ECMO enables stabilization and may rescue high-risk patients with refractory CS at low overall risk. Independent predictors of survival may guide prognostication, decision-making, and allocation of medical resources.