Readmissions to Hospital After Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis of Factors Associated with Readmissions.

BACKGROUND: Readmissions after PCI are a burden to patients and health services that are not well understood. METHODS: A systematic review was performed to identify studies of readmission after PCI. Readmission rates and causes of readmission were examined and factors associated with 30-day readmissions were combined using meta-analyses. RESULTS: A total of 39 studies evaluated readmissions after PCI (6,569,690 patients, 31 studies). The 30-day readmission rate varied from 3.3%-15.8%. Beyond 30-days, the readmission rate was 6% at 2 months, 31.5% at 6 months, 18.6-50.4% at 12 months and 26.3-71% beyond 48 months. The pooled proportion of patients with cardiac cause for readmissions ranged from 4.6%-75.3%. The range of rates of 30-day readmissions for reinfarction/stent thrombosis, heart failure, chest pain and bleeding were 2.5%-9.5%, 5.9%-12%, 6.7-38.1% and 0.7-7.5%, respectively. Meta-analysis suggests that female gender (RR 1.25(1.20-1.30), I2 = 65.2%), diabetes (RR 1.22(1.20-1.25), I2 = 0%), heart failure (RR 1.43(CI 1.28-1.60), I2 = 92.8%), renal failure (RR 1.50(1.45-1.55), I2 = 0%), chronic lung disease (RR 1.34(1.26-1.44), I2 = 87.5%), peripheral artery disease (RR 1.20(1.15-1.25), I2 = 46.5%) and cancer (RR 1.35(1.15-1.58), I2 = 72.8%) were associated with 30-day readmissions. The average cost of unplanned and all 30-day readmissions has been reported to be $12,636 and $17,576, respectively. CONCLUSIONS: We estimate that 1 in 7 patients who undergo PCI are readmitted within 30-days and the rate can rise to up to 3 in 4 patients beyond 3 years. Interventions should be considered to reduce readmissions such as discharge checklists, evaluation of medication compliance at follow-up and prompt management when patients re-present to emergency department.

The Relationship of Body Mass Index to Percutaneous Coronary Intervention Outcomes: Does the Obesity Paradox Exist in Contemporary Percutaneous Coronary Intervention Cohorts? Insights From the British Cardiovascular Intervention Society Registry.

OBJECTIVES: The aims of this study were to examine the relationship between body mass index (BMI) and clinical outcomes following percutaneous coronary intervention (PCI) and to determine the relevance of different clinical presentations requiring PCI to this relationship. BACKGROUND: Obesity is a growing problem, and studies have reported a protective effect from obesity compared with normal BMI for adverse outcomes after PCI. METHODS: Between 2005 and 2013, 345,192 participants were included. Data were obtained from the British Cardiovascular Intervention Society registry, and mortality data were obtained through the U.K. Office of National Statistics. Multiple logistic regression was performed to determine the association between BMI group (<18.5, 18.5 to 24.9, 25 to 30 and >30 kg/m2) and adverse in-hospital outcomes and mortality. RESULTS: At 30 days post-PCI, significantly lower mortality was seen in patients with elevated BMIs (odds ratio [OR]: 0.86 [95% confidence interval (CI): 0.80 to 0.93] 0.90 [95% CI: 0.82 to 0.98] for BMI 25 to 30 and >30 kg/m2, respectively). At 1 year post-PCI, and up to 5 years post-PCI, elevated BMI (either overweight or obese) was an independent predictor of greater survival compared with normal weight (OR: 0.70 [95% CI: 0.67 to 0.73] and 0.73 [95% CI: 0.69 to 0.77], respectively, for 1 year; OR: 0.78 [95% CI: 0.75 to 0.81] and 0.88 [95% CI: 0.84 to 0.92], respectively, for 5 years). Similar reductions in mortality were observed for the analysis according to clinical presentation (stable angina, unstable angina or non-ST-segment elevation myocardial infarction, and ST-segment elevation myocardial infarction). CONCLUSIONS: A paradox regarding the independent association of elevated BMI with reduced mortality after PCI is still evident in contemporary U.K. practice. This is seen in both stable and more acute clinical settings.

Major Bleeding and Adverse Outcome following Percutaneous Coronary Intervention.

Advances in anti-thrombotic and anti-platelet therapies have improved outcomes in patients undergoing percutaneous coronary interventions (PCIs) through a reduction in ischaemic events, at the expense of peri-procedural bleeding complications. These may occur through either the access site through which the PCI was performed or through non-access-related sites. There are currently over 10 definitions of major bleeding events consisting of clinical events, changes in laboratory parameters and clinical outcomes, where different definitions will differentially influence the reported incidence of major bleeding events. Use of different major bleeding definitions has been shown to change the reported outcome of a number of therapeutic strategies in randomised controlled trials but as yet a universal bleeding definition has not gained widespread adoption in assessing the efficacy of such therapeutic interventions. Major bleeding complications are independently associated with adverse mortality and major adverse cardiovascular event (MACE) outcomes, irrespective of the definition of major bleeding used, with the worst outcomes associate with non-access-site related bleeds. We consider the mechanisms through which bleeding complications may affect longer-term outcomes and discuss bleeding avoidance strategies, including access site choice, pharmacological considerations and formal bleeding risk assessment to minimise such bleeding events.

Tissue factor pathway inhibitor blocks angiogenesis via its carboxyl terminus.

OBJECTIVE: Tissue factor pathway inhibitor (TFPI) is the primary regulator of the tissue factor (TF) coagulation pathway. As such, TFPI may regulate the proangiogenic effects of TF. TFPI may also affect angiogenesis independently of TF, through sequences within its polybasic carboxyl terminus (TFPI C terminus [TFPIct]). We aimed to determine the effects of TFPI on angiogenesis and the role of TFPIct. METHODS AND RESULTS: Transgenic overexpression of TFPI attenuated angiogenesis in the murine hindlimb ischemia model and an aortic sprout assay. In vitro, TFPI inhibited endothelial cell migration. Peptides within the human TFPIct inhibited endothelial cell cord formation and migration in response to vascular endothelial growth factor (VEGF) 165 but not VEGF121. Furthermore, exposure to human TFPIct inhibited the phosphorylation of VEGF receptor 2 at residue Lys951, a residue known to be critical for endothelial cell migration. Finally, systemic delivery of a murine TFPIct peptide inhibited angiogenesis in the hindlimb model. CONCLUSION: These data demonstrate an inhibitory role for TFPI in angiogenesis that is, in part, mediated through peptides within its carboxyl terminus. In addition to its known role as a TF antagonist, TFPI, via its carboxyl terminus, may regulate angiogenesis by directly blocking VEGF receptor 2 activation and attenuating the migratory capacity of endothelial cells.

Tissue factor pathway inhibitor as a multifunctional mediator of vascular structure.

Tissue factor pathway inhibitor (TFPI) is a potent regulator of tissue factor - factor VII-dependent activation of the tissue factor pathway. TFPI is a serine protease inhibitor that contains three Kunitz domains and a basic carboxyl terminus. TFPI is primarily expressed on endothelial cells, and murine models have demonstrated that its expression regulates vascular thrombosis. The localization of TFPI expression and the requirement for TFPI in development suggest a potential role in regulating vascular structure. Data from animal studies suggest that vascular expression of TFPI inhibits pathologic vascular remodeling and inhibits angiogenesis. The mechanism for these effects is diverse and includes tissue factor and factor Xa-dependent and -independent mechanisms.

Identification of a monocyte-predisposed hierarchy of hematopoietic progenitor cells in the adventitia of postnatal murine aorta.

BACKGROUND: Hematopoiesis originates from the dorsal aorta during embryogenesis. Although adult blood vessels harbor progenitor populations for endothelial and smooth muscle cells, it is not known if they contain hematopoietic progenitor or stem cells. Here, we hypothesized that the arterial wall is a source of hematopoietic progenitor and stem cells in postnatal life. METHODS AND RESULTS: Single-cell aortic disaggregates were prepared from adult chow-fed C57BL/6 and apolipoprotein E-null (ApoE(-/-)) mice. In short- and long-term methylcellulose-based culture, aortic cells generated a broad spectrum of multipotent and lineage-specific hematopoietic colony-forming units, with a preponderance of macrophage colony-forming units. This clonogenicity was higher in lesion-free ApoE(-/-) mice and localized primarily to stem cell antigen-1-positive cells in the adventitia. Expression of stem cell antigen-1 in the aorta colocalized with canonical hematopoietic stem cell markers, as well as CD45 and mature leukocyte antigens. Adoptive transfer of labeled aortic cells from green fluorescent protein transgenic donors to irradiated C57BL/6 recipients confirmed the content of rare hematopoietic stem cells (1 per 4 000 000 cells) capable of self-renewal and durable, low-level reconstitution of leukocytes. Moreover, the predominance of long-term macrophage precursors was evident by late recovery of green fluorescent protein-positive colonies from recipient bone marrow and spleen that were exclusively macrophage colony-forming units. Although trafficking from bone marrow was shown to replenish some of the hematopoietic potential of the aorta after irradiation, the majority of macrophage precursors appeared to arise locally, suggesting long-term residence in the vessel wall. CONCLUSIONS: The postnatal murine aorta contains rare multipotent hematopoietic progenitor/stem cells and is selectively enriched with stem cell antigen-1-positive monocyte/macrophage precursors. These populations may represent novel, local vascular sources of inflammatory cells.

Resident vascular progenitor cells--diverse origins, phenotype, and function.

The fundamental contributions that blood vessels make toward organogenesis and tissue homeostasis are reflected by the considerable ramifications that loss of vascular wall integrity has on pre- and postnatal health. During both neovascularization and vessel wall remodeling after insult, the dynamic nature of vascular cell growth and replacement vitiates traditional impressions that blood vessels contain predominantly mature, terminally differentiated cell populations. Recent discoveries have verified the presence of diverse stem/progenitor cells for both vascular and non-vascular progeny within the mural layers of the vasculature. During embryogenesis, this encompasses the emergence of definitive hematopoietic stem cells and multipotent mesoangioblasts from the developing dorsal aorta. Ancestral cells have also been identified and isolated from mature, adult blood vessels, showing variable capacity for endothelial, smooth muscle, and mesenchymal differentiation. At present, the characterization of these different vascular wall progenitors remains somewhat rudimentary, but there is evidence for their constitutive residence within organized compartments in the vessel wall, most compellingly in the tunica adventitia. This review overviews the spectrum of resident stem/progenitor cells that have been documented in macro- and micro-vessels during developmental and adult life and considers the implications for a local, vascular wall stem cell niche(s) in the pathogenesis and treatment of cardiovascular and other diseases.

Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis.

The antithrombotic surface of endothelium is regulated in a coordinated manner. Tissue factor pathway inhibitor (TFPI) localized at the endothelial cell surface regulates the production of FXa by inhibiting the TF/VIIa complex. Systemic homozygotic deletion of the first Kunitz (K1) domain of TFPI results in intrauterine lethality in mice. Here we define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis using TFPI conditional knockout mice. We used a Cre-lox strategy and generated mice with a floxed exon 4 (TFPI(Flox)) which encodes for the TFPI-K1 domain. Mice bred into Tie2-Cre and LysM-Cre lines to delete TFPI-K1 in endothelial (TFPI(Tie2)) and myelomonocytic (TFPI(LysM)) cells resulted in viable and fertile offspring. Plasma TFPI activity was reduced in the TFPI(Tie2) (71% ± 0.9%, P < .001) and TFPI(LysM) (19% ± 0.6%, P < .001) compared with TFPI(Flox) littermate controls. Tail and cuticle bleeding were unaffected. However, TFPI(Tie2) mice but not TFPI(LysM) mice had increased ferric chloride-induced arterial thrombosis. Taken together, the data reveal distinct roles for endothelial- and myelomonocytic-derived TFPI.

Interdependent biological systems, multi-functional molecules: the evolving role of tissue factor pathway inhibitor beyond anti-coagulation.

Coagulation, innate immunity, angiogenesis, and lipid metabolism represent fundamental and interdependent biological systems. While tissue factor pathway inhibitor (TFPI) is the major physiological inhibitor of TF, its unique structure and endothelial expression allow multi-modal interactions with constituent molecules in each of these systems. We review emerging data describing roles for TFPI beyond simply opposing the action of TF, particularly with regard to the highly basic c-terminus of TFPI, and highlight potentially exciting new areas for future research.

Tissue factor pathway inhibitor overexpression inhibits hypoxia-induced pulmonary hypertension.

Pulmonary hypertension (PH) is a commonly recognized complication of chronic respiratory disease. Enhanced vasoconstriction, pulmonary vascular remodeling, and in situ thrombosis contribute to the increased pulmonary vascular resistance observed in PH associated with hypoxic lung disease. The tissue factor pathway regulates fibrin deposition in response to acute and chronic vascular injury. We hypothesized that inhibition of the tissue factor pathway would result in attenuation of pathophysiologic parameters typically associated with hypoxia-induced PH. We tested this hypothesis using a chronic hypoxia-induced murine model of PH using mice that overexpress tissue factor pathway inhibitor (TFPI) via the smooth muscle-specific promoter SM22 (TFPI(SM22)). TFPI(SM22) mice have increased pulmonary TFPI expression compared with wild-type (WT) mice. In WT mice, exposure to chronic hypoxia (28 d at 10% O(2)) resulted in increased systolic right ventricular and mean pulmonary arterial pressures, changes that were significantly reduced in TFPI(SM22) mice. Chronic hypoxia also resulted in significant pulmonary vascular muscularization in WT mice, which was significantly reduced in TFPI(SM22) mice. Given the pleiotropic effects of TFPI, autocrine and paracrine mechanisms for these hemodynamic effects were considered. TFPI(SM22) mice had less pulmonary fibrin deposition than WT mice at 3 days after exposure to hypoxia, which is consistent with the antithrombotic effects of TFPI. Additionally, TFPI(SM22) mice had a significant reduction in the number of proliferating (proliferating cell nuclear antigen positive) pulmonary vascular smooth muscle cells compared with WT mice, which is consistent with in vitro findings. These findings demonstrate that overexpression of TFPI results in improved hemodynamic performance and reduced pulmonary vascular remodeling in a murine model of hypoxia-induced PH. This improvement is in part due to the autocrine and paracrine effects of TFPI overexpression.