2016 Jeffrey M. Hoeg Award Lecture: Immune Checkpoints in Atherosclerosis: Toward Immunotherapy for Atheroprotection

Innate and adaptive immune effector mechanisms, in conjunction with hyperlipidemia, are important drivers of atherosclerosis. The interaction between the different immune cells and the secretion of cytokines and chemokines determine the progression of atherosclerosis. The activation or dampening of the immune response is tightly controlled by immune checkpoints. Costimulatory and coinhibitory immune checkpoints represent potential targets for immune modulatory therapies for atherosclerosis. This review will discuss the current knowledge on immune checkpoints in atherosclerosis and the clinical potential of immune checkpoint targeted therapy for atherosclerosis

農産物市場研究ノ必要ヲ論ズ

Objectives: The aim of this study was to assess the vitamin D status in patients with occlusive or aneurysmatic arterial disease in relation to clinical cardiovascular risk profiles and markers of atherosclerotic disease. Methods: We included 490 patients with symptomatic peripheral arterial disease (PAD, n = 254) or aortic aneurysm (n = 236). Cardiovascular risk factors and comorbidities carotid intima-media thickness (CIMT), ankle-brachial index (ABI), serum high-sensitive C-reactive protein (hs-CRP) and vitamin D were assessed. Patients were categorised into severely (≤25 nmol l -1) or moderately (26-50 nmol l -1) vitamin D deficient, vitamin D insufficient (51-75 nmol l -1) or vitamin D sufficient (>75 nmol l -1). Results: Overall, 45% of patients suffered from moderate or severe vitamin D deficiency. The prevalence of vitamin D deficiency was similar in patients with PAD and those with an aortic aneurysm. Low levels of vitamin D were associated with congestive heart failure and cerebrovascular disease. Adjusting for clinical cardiovascular risk factors, multivariable regression analyses showed that low vitamin D status was associated with higher CIMT (P = 0.001), lower ABI (P < 0.001) and higher hs-CRP (P = 0.022). Conclusions: The current study shows a strong association between low vitamin D status and arterial disease, independent of traditional cardiovascular risk factors and irrespective of the type of vascular disease, that is, occlusive or aneurysmatic disease

Introducing the Concept of the Minimally Important Difference to Determine a Clinically Relevant Change on Patient-Reported Outcome Measures in Patients with Intermittent Claudication

Purpose: The minimally important difference (MID) represents the smallest change in score on patient-reported outcome measures that is relevant to patients. The aim of this study was to introduce the MID for the Vascular Quality of Life Questionnaire (VascuQol) and the walking impairment questionnaire (WIQ) for patients with intermittent claudication (IC). Methods: In this multicenter study, we recruited 294 patients with IC between July and October 2012. Patients completed the VascuQol, with scores ranging from 1 to 7 (worst to best), and the WIQ, with scores ranging from 0 to 1 (worst to best) at first visit and after 4 months follow-up. In addition, patients answered an anchor-question rating their health status compared to baseline, as being improved, unchanged, or deteriorated. The MID for improvement and deterioration was calculated by an anchor-based approach, and determined with the upper and lower limits of the 95 % confidence interval of the mean change of the group who had not changed according to the anchor-question. Results: For the MID analyses of the VascuQol and WIQ, 163 and 134 patients were included, respectively. The MID values for the VascuQol (mean baseline score 4.25) were 0.87 for improvement and 0.23 for deterioration. For the WIQ (mean baseline score 0.39), we found MID values of 0.11 and −0.03 for improvement and deterioration, respectively. Conclusion: In this study, we calculated the MID for the VascuQol and the WIQ. Applying these MID facilitates better interpretation of treatment outcomes and can help to set treatment goals for individual care

Supervised exercise therapy and revascularization: Single-center experience of intermittent claudication management

Guidelines recommend supervised exercise therapy (SET) as first-line treatment for intermittent claudication. However, the use of revascularization is widespread. We addressed the effectiveness of preventing (additional) invasive revascularization after primary SET or revascularization based on lesion and patient characteristics. In this single-center, retrospective, cohort study, 474 patients with intermittent claudication were included. Patients with occlusive disease of the aortoiliac tract and/or common femoral artery (inflow) were primarily considered for revascularization, while patients with more distal disease (outflow) were primarily considered for SET. In total, 232 patients were referred for SET and 242 patients received revascularization. The primary outcome was freedom from (additional) intervention, analyzed by Kaplan–Meier estimates. Secondary outcomes were survival, critical ischemia, freedom from target lesion revascularization (TLR), and an increase in maximum walking distance. In the SET-first strategy, 71% of patients had significant outflow lesions. Freedom from intervention was 0.90 ± 0.02 at 1-year and 0.82 ± 0.03 at 2-year follow-up. In the primary revascularization group, 90% of patients had inflow lesions. Freedom from additional intervention was 0.78 ± 0.03 at 1-year and only 0.65 ± 0.04 at 2-year follow-up, despite freedom from TLR of 0.91 ± 0.02 and 0.85 ± 0.03 at 1- and 2-year follow-up, respectively. In conclusion, SET was effective in preventing invasive treatment for patients with mainly outflow lesions. In contrast, secondary intervention rates following our strategy of primary revascularization for inflow lesions were unexpectedly high. These findings further support the guideline recommendations of SET as first-line treatment for all patients with intermittent claudication irrespective of level of disease

Type D Personality and Health-Related Quality of Life in Vascular Surgery Patients

Background: This study evaluated the association of type D personality and health-related quality of life (HRQoL) and assessed the stability of type D personality in vascular surgery patients during the year after surgery. Method: In a prospective cohort study between 2008 and 2014, 294 patients were assessed with validated questionnaires preoperatively and at 1, 6, and 12 months after surgery. Associations between type D personality, depression, and HRQoL were analyzed by generalized estimating equation models. Type D personality was analyzed in its standard dichotomous form as well as continuous (z) scores of its two components, negative affectivity (NA) and social inhibition (SI), and their interaction term. Results: Prevalence of type D personality varied between 18% and 25%. However, only 9% of the complete responders were classified as type D personality at all four assessments, whereas one third changed between type D classifications. Continuous scores showed greater stability over time. Dichotomized type D personality measured over time was significantly associated with impaired HRQoL, but this was not the case if measured once at baseline, like in general use. The continuous NA score and depression were also significantly associated with impaired HRQoL over time. Conclusion: Type D personality was not a stable trait over time. Preoperative assessment of type D personality did not predict improvement in HRQoL after vascular surgery. However, the study revealed associations between the NA component of type D personality, depression, and lower HRQoL. This indicates that measures of overall negative affect should be taken into account when assessing HRQoL patient-reported outcomes in vascular surgery patients

The effect of a community-based group intervention on chronic disease self-management in a vulnerable population

Introduction:Chronic non-communicable diseases (NCDs) are predominantly related to modifiable health behaviors and account for 74% of global deaths at present. Behavior modification through self-management is a strategy to prevent NCDs. Chronic Disease Self-Management Programs (CDSMPs) have demonstrated improvements in health behaviors, health status, and use of healthcare. Objective:We evaluated the effects of a 6-week CDSMP on self-efficacy, health behaviors, mental health, health-related quality of life (HR-QoL), and health responsibilities among vulnerable populations with chronic disease in Europe. Methods: A prospective cohort study with a 6-month pre-post single-group design was conducted in five European countries. The intervention targeted adults with chronic conditions and low socioeconomic status, as well as their caregivers. The intervention was a 6-week community-based CDSMP in a group setting. Outcomes were measured per self-report questionnaire at baseline and 6-month follow-up: self-efficacy, health behaviors, mental health, HR-QoL, and health responsibilities. Results: Of 1,844 participants, 1,248 (67.7%) completed follow-up and attended ≥4 sessions. For the chronic condition group, the following outcome measures at follow-up significantly improved compared with baseline (all P &lt; 0.002): self-efficacy (SEMCD-6 6.7 vs. 6.4), mental health (PHQ-8 6.3 vs. 7.0), HR-QoL (SF-12 PCS 42.3 vs. 40.2, SF-12 MCS 42.8 vs. 41.4), health utility (EQ-5D-5L 0.88 vs. 0.86), self-rated health (EQ-5D-5L 67.2 vs. 63.9), communication with healthcare providers (2.28 vs. 2.11), understanding information (3.10 vs. 3.02), number of doctor visits (3.61 vs. 4.97), accident and emergency department visits (0.25 vs. 0.48), total nights in a hospital (0.65 vs. 1.13), and perceived medical errors (19.6 vs. 28.7%). No significant changes were detected in dietary habits, physical activity, substance use, and sleep and fatigue. For caregivers without a chronic condition, only doctor visits significantly decreased (1.54 vs. 2.25, P &lt; 0.001). Discussion: This CDSMP was associated with improvement in self-efficacy, depression, HR-QoL, and health responsibilities over 6 months in a diverse European population with a chronic condition. However, additional interventions targeting lifestyle risk factors are needed to improve health outcomes.</p

Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences

Background: Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos. Methods: Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine. Principal Findings: Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype. Conclusions/Significance: Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood

Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism; intervention; and long-term consequences.

Background Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos. Methods Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine. Principal Findings Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype. Conclusions/Significance Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood